Quinazolines useful as modulators of ion channels

ABSTRACT

The present invention relates to compounds useful as inhibitors of voltage-gated sodium channels. The invention also provides pharmaceutically acceptable compositions comprising the compounds of the invention and methods of using the compositions in the treatment of various disorders.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application, as a continuation-in-part application, claims thebenefit under 35 U.S.C. §120 of U.S. patent application Ser. No.11/216,376, filed Aug. 31, 2005, entitled “Quinazolines Useful asModulators of Ion Channels” and of International Patent applicationnumber PCT/US2005/31146, filed Aug. 31, 2005 entitled “QuinazolinesUseful as Modulators of Ion Channels”, both of which claim the benefitunder 35 U.S.C. §119 to U.S. Provisional application Ser. No.60/607,150, filed Sep. 2, 2004, U.S. Provisional application Ser. No.60/607,037, filed Sep. 2, 2004, U.S. Provisional application Ser. No.60/607,033, filed Sep. 2, 2004, and U.S. Provisional application Ser.No. 60/607,036, filed Sep. 2, 2004, the entire contents of each of theabove applications being incorporated herein by reference.

TECHNICAL FIELD OF THE INVENTION

The present invention relates to compounds useful as inhibitors of ionchannels. The invention also provides pharmaceutically acceptablecompositions comprising the compounds of the invention and methods ofusing the compositions in the treatment of various disorders.

BACKGROUND OF THE INVENTION

Na channels are central to the generation of action potentials in allexcitable cells such as neurons and myocytes. They play key roles inexcitable tissue including brain, smooth muscles of the gastrointestinaltract, skeletal muscle, the peripheral nervous system, spinal cord andairway. As such they play key roles in a variety of disease states suchas epilepsy (ee, Moulard, B. and D. Bertrand (2002) “Epilepsy and sodiumchannel blockers” Expert Opin. Ther. Patents 12(1): 85-91)), pain (See,Waxman, S. G., S. Dib-Hajj, et al. (1999) “Sodium channels and pain”Proc Natl Acad Sci USA 96(14): 7635-9 and Waxman, S. G., T. R. Cummins,et al. (2000) “Voltage-gated sodium channels and the molecularpathogenesis of pain: a review” J Rehabil Res Dev 37(5): 517-28),myotonia (See, Meola, G. and V. Sansone (2000) “Therapy in myotonicdisorders and in muscle channelopathies” Neurol Sci 21(5): S953-61 andMankodi, A. and C. A. Thornton (2002) “Myotonic syndromes” Curr OpinNeurol 15(5): 545-52), ataxia (See, Meisler, M. H., J. A. Kearney, etal. (2002) “Mutations of voltage-gated sodium channels in movementdisorders and epilepsy” Novartis Found Symp 241: 72-81), multiplesclerosis (See, Black, J. A., S. Dib-Hajj, et al. (2000) “Sensoryneuron-specific sodium channel SNS is abnormally expressed in the brainsof mice with experimental allergic encephalomyelitis and humans withmultiple sclerosis” Proc Natl Acad Sci USA 97(21): 11598-602, andRenganathan, M., M. Gelderblom, et al. (2003) “Expression of Na(v)1.8sodium channels perturbs the firing patterns of cerebellar purkinjecells” Brain Res 959(2): 235-42), irritable bowel (See Su, X., R. E.Wachtel, et al. (1999) “Capsaicin sensitivity and voltage-gated sodiumcurrents in colon sensory neurons from rat dorsal root ganglia” Am JPhysiol 277(6 Pt 1): G1180-8, and Laird, J. M., V. Souslova, et al.(2002) “Deficits in visceral pain and referred hyperalgesia in Nav1.8(SNS/PN3)-null mice” J Neurosci 22(19): 8352-6), urinary incontinenceand visceral pain (See, Yoshimura, N., S. Seki, et al. (2001) “Theinvolvement of the tetrodotoxin-resistant sodium channel Na(v)1.8(PN3/SNS) in a rat model of visceral pain” J Neurosci 21(21): 8690-6),as well as an array of psychiatry dysfunctions such as anxiety anddepression (See, Hurley, S. C. (2002) “Lamotrigine update and its use inmood disorders” Ann Pharmacother 36(5): 860-73).

Voltage gated Na channels comprise a gene family consisting of 9different subtypes (NaV1.1-NaV1.9). These subtypes show tissue specificlocalization and functional differences (See, Goldin, A. L. (2001)“Resurgence of sodium channel research” Annu Rev Physiol 63: 871-94).Three members of the gene family (NaV1.8, 1.9, 1.5) are resistant toblock by the well-known Na channel blocker TTX, demonstrating subtypespecificity within this gene family. Mutational analysis has identifiedglutamate 387 as a critical residue for TTX binding (See, Noda, M., H.Suzuki, et al. (1989) “A single point mutation confers tetrodotoxin andsaxitoxin insensitivity on the sodium channel II” FEBS Lett 259(1):213-6).

In general, voltage-gated sodium channels (NaVs) are responsible forinitiating the rapid upstroke of action potentials in excitable tissuein nervous system, which transmit the electrical signals that composeand encode normal and aberrant pain sensations. Antagonists of NaVchannels can attenuate these pain signals and are useful for treating avariety of pain conditions, including but not limited to acute, chronic,inflammatory, and neuropathic pain. Known NaV antagonists, such as TTX,lidocaine (See Mao, J. and L. L. Chen (2000) “Systemic lidocaine forneuropathic pain relief” Pain 87(1): 7-17.) bupivacaine, phenyloin (See,Jensen, T. S. (2002) “Anticonvulsants in neuropathic pain: rationale andclinical evidence” Eur J Pain 6 (Suppl A): 61-8), lamotrigine (See,Rozen, T. D. (2001) “Antiepileptic drugs in the management of clusterheadache and trigeminal neuralgia” Headache 41 Suppl 1: S25-32 andJensen, T. S. (2002) “Anticonvulsants in neuropathic pain: rationale andclinical evidence” Eur J Pain 6 (Suppl A): 61-8), and carbamazepine(See, Backonja, M. M. (2002) “Use of anticonvulsants for treatment ofneuropathic pain” Neurology 59(5 Suppl 2): S14-7), have been shown to beuseful attenuating pain in humans and animal models.

Hyperalgesia (extreme sensitivity to something painful) that develops inthe presence of tissue injury or inflammation reflects, at least inpart, an increase in the excitability of high-threshold primary afferentneurons innervating the site of injury. Voltage sensitive sodiumchannels activation is critical for the generation and propagation ofneuronal action potentials. There is a growing body of evidenceindicating that modulation of NaV currents is an endogenous mechanismused to control neuronal excitability (See, Goldin, A. L. (2001)“Resurgence of sodium channel research” Annu Rev Physiol 63: 871-94).Several kinetically and pharmacologically distinct voltage-gated sodiumchannels are found in dorsal root ganglion (DRG) neurons. TheTTX-resistant current is insensitive to micromolar concentrations oftetrodotoxin, and displays slow activation and inactivation kinetics anda more depolarized activation threshold when compared to othervoltage-gated sodium channels. TTX-resistant sodium currents areprimarily restricted to a subpopulation of sensory neurons likely to beinvolved in nociception. Specifically, TTX-resistant sodium currents areexpressed almost exclusively in neurons that have a small cell-bodydiameter; and give rise to small-diameter slow-conducting axons and thatare responsive to capsaicin. A large body of experimental evidencedemonstrates that TTX-resistant sodium channels are expressed onC-fibers and are important in the transmission of nociceptiveinformation to the spinal cord.

Intrathecal administration of antisense oligo-deoxynucleotides targetinga unique region of the TTX-resistant sodium channel (NaV1.8) resulted ina significant reduction in PGE₂-induced hyperalgesia (See, Khasar, S.G., M. S. Gold, et al. (1998) “A tetrodotoxin-resistant sodium currentmediates inflammatory pain in the rat” Neurosci Lett 256(1): 17-20).More recently, a knockout mouse line was generated by Wood andcolleagues, which lacks functional NaV1.8. The mutation has an analgesiceffect in tests assessing the animal's response to the inflammatoryagent carrageenan (See, Akopian, A. N., V. Souslova, et al. (1999) “Thetetrodotoxin-resistant sodium channel SNS has a specialized function inpain pathways” Nat Neurosci 2(6): 541-8). In addition, deficit in bothmechano- and thermoreception were observed in these animals. Theanalgesia shown by the Nav1.8 knockout mutants is consistent withobservations about the role of TTX-resistant currents in nociception.

Immunohistochemical, in-situ hybridization and in-vitroelectrophysiology experiments have all shown that the sodium channelNaV1.8 is selectively localized to the small sensory neurons of thedorsal root ganglion and trigeminal ganglion (See, Akopian, A. N., L.Sivilotti, et al. (1996) “A tetrodotoxin-resistant voltage-gated sodiumchannel expressed by sensory neurons” Nature 379(6562): 257-62). Theprimary role of these neurons is the detection and transmission ofnociceptive stimuli. Antisense and immunohistochemical evidence alsosupports a role for NaV1.8 in neuropathic pain (See, Lai, J., M. S.Gold, et al. (2002) “Inhibition of neuropathic pain by decreasedexpression of the tetrodotoxin-resistant sodium channel, NaV1.8” Pain95(1-2): 143-52, and Lai, J., J. C. Hunter, et al. (2000) “Blockade ofneuropathic pain by antisense targeting of tetrodotoxin-resistant sodiumchannels in sensory neurons” Methods Enzymol 314: 201-13). NaV1.8protein is upregulated along uninjured C-fibers adjacent to the nerveinjury. Antisense treatment prevents the redistribution of NaV1.8 alongthe nerve and reverses neuropathic pain. Taken together thegene-knockout and antisense data support a role for NaV1.8 in thedetection and transmission of inflammatory and neuropathic pain.

Several Na channel blockers are currently used or being tested in theclinic to treat epilepsy (See, Moulard, B. and D. Bertrand (2002)“Epilepsy and sodium channel blockers” Expert Opin. Ther. Patents 12(1):85-91); acute (See, Wiffen, P., S. Collins, et al. (2000)“Anticonvulsant drugs for acute and chronic pain” Cochrane Database SystRev 3), chronic (See, Wiffen, P., S. Collins, et al. (2000)“Anticonvulsant drugs for acute and chronic pain” Cochrane Database SystRev 3, and Guay, D. R. (2001) “Adjunctive agents in the management ofchronic pain” Pharmacotherapy 21(9): 1070-81), inflammatory (See, Gold,M. S. (1999) “Tetrodotoxin-resistant Na+ currents and inflammatoryhyperalgesia.” Proc Natl Acad Sci USA 96(14): 7645-9), and neuropathicpain (See, Strichartz, G. R., Z. Zhou, et al. (2002) “Therapeuticconcentrations of local anaesthetics unveil the potential role of sodiumchannels in neuropathic pain” Novartis Found Symp 241: 189-201, andSandner-Kiesling, A., G. Rumpold Seitlinger, et al. (2002) “Lamotriginemonotherapy for control of neuralgia after nerve section” ActaAnaesthesiol Scand 46(10): 1261-4); cardiac arrhythmias (See, An, R. H.,R. Bangalore, et al. (1996) “Lidocaine block of LQT-3 mutant human Na⁺channels” Circ Res 79(1): 103-8, and Wang, D. W., K. Yazawa, et al.(1997) “Pharmacological targeting of long QT mutant sodium channels” JClin Invest 99(7): 1714-20); neuroprotection (ee Taylor, C. P. and L. S,Narasimhan (1997) “Sodium channels and therapy of central nervous systemdiseases” Adv Pharmacol 39: 47-98) and as anesthetics (See, Strichartz,G. R., Z. Zhou, et al. (2002) “Therapeutic concentrations of localanaesthetics unveil the potential role of sodium channels in neuropathicpain.” Novartis Found Symp, 241: 189-201).

Various animal models with clinical significance have been developed forthe study of sodium channel modulators for numerous different painindications. E.g., malignant chronic pain, see, Kohase, H., et al., ActaAnaesthesiol Scand. 2004; 48(3):382-3; femur cancer pain (see, Kohase,H., et al., Acta Anaesthesiol Scand. 2004; 48(3):382-3); non-malignantchronic bone pain (see, Ciocon, J. O. et al., J Am Geriatr Soc. 1994;42(6):593-6); rheumatoid arthritis (see, Calvino, B. et al., Behav BrainRes. 1987; 24(1):11-29); osteoarthritis (see, Guzman, R. E., et al.,Toxicol Pathol. 2003; 31(6):619-24); spinal stenosis (see, Takenobu, Y.et al., J Neurosci Methods. 2001; 104(2):191-8); Neuropathic low backpain (see, Hines, R., et al., Pain Med. 2002; 3(4):361-5; Massie, J. B.,et al., J Neurosci Methods. 2004; 137(2):283-9; neuropathic lowback-pain (see, Hines, R., et al., Pain Med. 2002; 3(4):361-5; Massie,J. B., et al., J Neurosci Methods. 2004; 137(2):283-9); myofascial painsyndrome (see, Dalpiaz & Dodds, J Pain Palliat Care Pharmacother. 2002;16(1):99-104; Sluka K A et al., Muscle Nerve. 2001; 24(1):37-46);fibromyalgia (see, Bennet & Tai, Int J Clin Pharmacol Res. 1995;15(3):115-9); temporomandibular joint pain (see, Ime H, Ren K, Brain ResMol Brain Res. 1999; 67(1):87-97); chronic visceral pain, including,abdominal (see, Al-Chaer, E. D., et al., Gastroenterology. 2000;119(5):1276-85); pelvic/perineal pain, (see, Wesselmann et al., NeurosciLett. 1998; 246(2):73-6); pancreatic (see, Vera-Portocarrero, L. B., etal., Anesthesiology. 2003; 98(2):474-84); IBS pain (see, Verne, G. N.,et al., Pain. 2003; 105(1-2):223-30; La J H et al., World Gastroenterol.2003; 9(12):2791-5); chronic headache pain (see, Willimas & Stark,Cephalalgia. 2003; 23(10):963-71); migraine (see, Yamamura, H., et al.,J. Neurophysiol. 1999; 81(2):479-93); tension headache, including,cluster headaches (see, Costa, A., et al., Cephalalgia. 2000;20(2):85-91); chronic neuropathic pain, including, post-herpeticneuralgia (see, Attal, N., et al., Neurology. 2004; 62(2):218-25; Kim &Chung 1992, Pain 50:355); diabetic neuropathy (see, Beidoun A et al.,Clin J. Pain. 2004; 20(3):174-8; Courteix, C., et al., Pain. 1993;53(1):81-8); HIV-associated neuropathy (see, Portegies & Rosenberg, NedTijdschr Geneeskd. 2001; 145(15):731-5; Joseph E K et al., Pain. 2004;107(1-2):147-58; Oh, S. B., et al., J. Neurosci. 2001; 21(14):5027-35);trigeminal neuralgia (see, Sato, J., et al., Oral Surg Oral Med OralPathol Oral Radiol Endod. 2004; 97(1):18-22; Imamura Y et al., Exp BrainRes. 1997; 116(1):97-103); Charcot-Marie Tooth neuropathy (see, Sereda,M., et al., Neuron. 1996; 16(5):1049-60); hereditary sensoryneuropathies (see, Lee, M. J., et al., Hum Mol. Genet. 2003;12(15):1917-25); peripheral nerve injury (see, Attal, N., et al.,Neurology. 2004; 62(2):218-25; Kim & Chung 1992, Pain 50:355; Bennett &Xie, 1988, Pain 33:87; Decostered, I. & Woolf, C. J., 2000, Pain 87:149;Shir, Y. & Seltzer, Z. 1990; Neurosci Lett 115:62); painful neuromas(see, Nahabedian & Johnson, Ann Plast Surg. 2001; 46(1):15-22; Devor &Raber, Behav Neural Biol. 1983; 37(2):276-83); ectopic proximal anddistal discharges (see, Liu, X. et al., Brain Res. 2001; 900(1):119-27);radiculopathy (see, Devers & Galer, (see, Clin J. Pain. 2000;16(3):205-8; Hayashi N et al., Spine. 1998; 23(8):877-85); chemotherapyinduced neuropathic pain (see, Aley, K. O., et al., Neuroscience. 1996;73(1):259-65); radiotherapy-induced neuropathic pain; post-mastectomypain (see, Devers & Galer, Clin J. Pain. 2000; 16(3):205-8); centralpain (Cahana, A., et al., Anesth Analg. 2004; 98(6):1581-4), spinal cordinjury pain (see, Hains, B. C., et al., Exp Neurol. 2000;164(2):426-37); post-stroke pain; thalamic pain (see, LaBuda, C. J., etal., Neurosci Lett. 2000; 290(1):79-83); complex regional pain syndrome(see, Wallace, M. S., et al., Anesthesiology. 2000; 92(1):75-83; XantosD et al., J. Pain. 2004; 5(3 Suppl 2):S1); phanton pain (see, Weber, W.E., Ned Tijdschr Geneeskd. 2001; 145(17):813-7; Levitt & Heyback, Pain.1981; 10(1):67-73); intractable pain (see, Yokoyama, M., et al., Can J.Anaesth. 2002; 49(8):810-3); acute pain, acute post-operative pain (see,Koppert, W., et al., Anesth Analg. 2004; 98(4):1050-5; Brennan, T. J.,et al., Pain. 1996; 64(3):493-501); acute musculoskeletal pain; jointpain (see, Gotoh, S., et al., Ann Rheum Dis. 1993; 52(11):817-22);mechanical low back pain (see, Kehl, L. J., et al., Pain. 2000;85(3):333-43); neck pain; tendonitis; injury/exercise pain (see, Sesay,M., et al., Can J. Anaesth. 2002; 49(2):137-43); acute visceral pain,including, abdominal pain; pyelonephritis; appendicitis; cholecystitis;intestinal obstruction; hernias; etc (see, Giambernardino, M. A., etal., Pain. 1995; 61(3):459-69); chest pain, including, cardiac Pain(see, Vergona, R. A., et al., Life Sci. 1984; 35(18):1877-84); pelvicpain, renal colic pain, acute obstetric pain, including, labor pain(see, Segal, S., et al., Anesth Analg. 1998; 87(4):864-9); cesareansection pain; acute inflammatory, burn and trauma pain; acuteintermittent pain, including, endometriosis (see, Cason, A. M., et al.,Horm Behav. 2003; 44(2):123-31); acute herpes zoster pain; sickle cellanemia; acute pancreatitis (see, Toma, H; Gastroenterology. 2000;119(5):1373-81); breakthrough pain; orofacial pain, including, sinusitispain, dental pain (see, Nusstein, J., et al., J. Endod. 1998;24(7):487-91; Chidiac, J. J., et al., Eur J. Pain. 2002; 6(1):55-67);multiple sclerosis (MS) pain (see, Sakurai & Kanazawa, J Neurol Sci.1999; 162(2):162-8); pain in depression (see, Greene B, Curr Med ResOpin. 2003; 19(4):272-7); leprosy pain; behcet's disease pain; adiposisdolorosa (see, Devillers & Oranje, Clin Exp Dermatol. 1999;24(3):240-1); phlebitic pain; Guillain-Barre pain; painful legs andmoving toes; Haglund syndrome; erythromelalgia pain (see,Legroux-Crespel, E., et al., Ann Dermatol Venereol. 2003;130(4):429-33); Fabry's disease pain (see, Germain, D. P., J Soc Biol.2002; 196(2):183-90); Bladder and urogenital disease, including, urinaryincontinence (see, Berggren, T., et al., J. Urol. 1993; 150(5 Pt1):1540-3); hyperactivity bladder (see, Chuang, Y. C., et al., Urology.2003; 61(3):664-70); painful bladder syndrome (see, Yoshimura, N., etal., J. Neurosci. 2001; 21(21):8690-6); interstitial cyctitis (IC) (see,Giannakopoulos& Campilomatos, Arch Ital Urol Nefrol Androl. 1992;64(4):337-9; Boucher, M., et al., J. Urol. 2000; 164(1):203-8); andprostatitis (see, Mayersak, J. S., Int Surg. 1998; 83(4):347-9; Keith,I. M., et al., J. Urol. 2001; 166(1):323-8).

Unfortunately, as described above, the efficacy of currently used sodiumchannel blockers and calcium channel blockers for the disease statesdescribed above has been to a large extent limited by a number of sideeffects. These side effects include various CNS disturbances such asblurred vision, dizziness, nausea, and sedation as well more potentiallylife threatening cardiac arrhythmias and cardiac failure. Suchundesirable side effects may be avoided by using a Na channel blockerthat exhibit a degree of selectivity in its activity against a Nachannel subtype. However, Na channel blockers currently in the marketlack such selectivity. Perhaps because of this lack of molecularselectivity, drugs currently in the market exhibit use-dependent blockand generally show higher affinity at depolarized potentials resultingin the preferential targeting of actively firing neurons, believed to bea key factor in the therapeutic window of existing Na channel blockingdrugs. While every drug has it own unique therapeutic profile, currentNa channel blockers are generally associated with central nervous system(CNS) and cardiovascular (CV) side effects, including blood pressurechanges, which are often dose-limiting. Dizziness, sedation, nausea,ataxia, and confusion are some of the specific side effects observed forPhenyloin™, Mexiletine™, and Lidocaine™.

There is also a need to develop Na channel blockers that have minimal orno inhibitory activity against the hERG channel. hERG (human ethera-go-go related gene) encodes a potassium ion channel (hERG channel)that is involved in cardiac repolarization. See, e.g., Pearlstein, R.,R. Vaz, et al. (2003). “Understanding the Structure-ActivityRelationship of the Human Ether-a-go-go-Related Gene Cardiac K(+)Channel. A Model for Bad Behavior.” J Med Chem 46(11): 2017-22.Interaction with the hERG channel is one indicator of potential cardiactoxicity. hERG-block increases the likelihood of cardiac QT-intervalprolongation and dispersion. A subset of compounds that prolong the QTinterval can cause ventricular fibrillation and cardiac failure.Belardinelli, L., C. Antzelevitch and M. A. Vos (2003). “Assessingpredictors of drug-induced torsade de pointes”. Trends Pharmacol Sci. 24(12): 619-25; Al-Khatib, S. M., N. M. LaPointe, et al. (2003). “Whatclinicians should know about the QT interval.” Jama 289(16): 2120-7;http://www.fenichel.net/pages/site_map.htm.

There is also a need to develop Na channel blockers that have minimal orno inhibitory activity against the Cytochrome P450 enzyme family. Withinthis family, CYP 3A4 isoform is believed to be the major isoform presentin the liver and small intestines. Other key isoforms include CYP 2D6,CYP 2C9, and CYP 1A2. See, e.g., U.S. Pat. No. 6,514,687, the disclosurewhereof is incorporated herein by reference. A Na channel blocker thatinhibits one or more of the isoforms can cause undesirable side effector can cause undesirable drug-drug interactions when administered withanother drug that interacts with that isoform. See, e.g., Davit, B., etal. (1999), “FDA Evaluations Using In Vitro Metabolism to Predict andInterpret In Vivo Metabolic Drug-Drug Interactions: Impact on Labeling,”J. Clin. Pharmacol., 39: 899-910; “Drug Metabolism/Drug InteractionStudies in the Drug Development Process: Studies In Vitro, Dept. ofHealth and Human Services, U.S.F.D.A(http://www.fda.gov/cder/guidance.htm).

There is also a need to develop Na channel blockers that exhibitselectivity against a certain sub-type of Na channel. Particularlyuseful are compounds that have a desirably low activity against NaV 1.2.

There is also a need to develop Na channel blockers that have adesirably low activity against L-type calcium channel 1.2. CaV1.2calcium channels are abundantly expressed in smooth and striated muscle,especially in the heart, brain and endocrine cells. Blocking thesechannels can be therapeutically useful, but it can also result insignificant side effects. The most significant concerns are impairmentof cardiac contractility (that is, a negative inotropic effect) andslowing of electrical conduction in the pacemaker regions of the heart.See, e.g., Kizer, J. R., et al., “Epidemiologic Review of the CalciumChannel Blocker Drugs,” Arch. Intern Med. 2001; 161: 1145-1158.

There is also a need to Na channel blockers that have a desirably lowactivity against potassium channel 1.5 (“Kv1.5”; also known as KCNA5).Kv1.5 is found primarily in human atrial cells, but also in brain. See,e.g., Gutman, G. A., et al., “Compendium of Voltage-Gated Ion ChannelsPotassium Channels,” Pharmacol. Rev., 55: 583-585 (2003). Unwanted blockof Kv1.5 could produce convulsion or ataxia.

There is also a need to develop Na channel blockers that have improvedpharmacokinetic and/or pharmacodynamic properties and, therefore, arebetter suited for in-vivo administration for therapeutic purposes. Suchproperties include aqueous solubility, bioavailability, clearancekinetics, etc. See, e.g., Shargel, L., Yu, A., Ed's “AppliedBiopharmaceutics & Pharmacokinetics”, 4th Ed., McGraw-Hill, New York,1999; Yacobi, A., Skelly, J. P., Shah, V. P., Benet, L. Z., Ed's.“Integration of Pharmacokinetics, Pharmacodynamics, and Toxicokineticsin Rational Drug Development”, Plenum Press, New York, 1993; Lee, J. S.,Obach, R. S., Fisher, M. B., Ed's. “Drug Metabolizing Enzymes CytochromeP450 and Other Enzymes in Drug Discovery and Development”, MarcelDekker, New York, 2003; Birkett, D. J. “Pharmacokinetics Made Easy”,McGraw-Hill Australia, Roseville, Australia, 2002; Katzung, B. G. “Basic& Clinical Pharmacology”, McGraw-Hill, New York, 2001; Welling, P. G.,Tse, F. L. S., Ed's. “Pharmcokinetics”, Marcel Dekker, New York, 1988;Thomas, G. “Medicinal Chemistry An Introduction”, Wiley & Sons, NewYork, 2000; and Gennaro, A. R., et al., “Remington: The Science andPractice of Pharmacy,” 20^(th) Ed., Lippincott, Williams, & Wilkins(2003).

A Na channel blocker that meets one or more of the above unmet needswould be a very desirable improvement over the currently marketed Nachannel blockers and would greatly benefit patients in need of a therapytherewith.

SUMMARY OF THE INVENTION

The present invention provides compounds of formula I:

-   -   or a pharmaceutically acceptable salt or derivative thereof.

These compounds and pharmaceutically acceptable compositions are usefulfor treating or lessening the severity of a variety of diseases,disorders, or conditions, including, but not limited to, acute, chronic,neuropathic, or inflammatory pain, arthritis, migraine, clusterheadaches, trigeminal neuralgia, herpetic neuralgia, general neuralgias,epilepsy or epilepsy conditions, neurodegenerative disorders,psychiatric disorders such as anxiety and depression, myotonia,arrhythmia, movement disorders, neuroendocrine disorders, ataxia,multiple sclerosis, irritable bowel syndrome, incontinence, visceralpain, osteoarthritis pain, postherpetic neuralgia, diabetic neuropathy,radicular pain, sciatica, back pain, head or neck pain, severe orintractable pain, nociceptive pain, breakthrough pain, postsurgicalpain, or cancer pain.

DETAILED DESCRIPTION OF THE INVENTION I. General Description ofCompounds of the Invention

The present invention provides a compound of formula I:

-   -   or a pharmaceutically acceptable salt or derivative thereof,        wherein:    -   R¹ and R², taken together with the nitrogen atom, form a        substituted ring selected from:

wherein, in ring (A):

-   -   each of m₁ and n₁ is independently 0-3, provided that m₁+n₁ is        2-6;    -   z₁ is 0-4;    -   Sp¹ is —O—, —S—, —NR′—, or a C1-C6 alkylidene linker, wherein up        to two methylene units are optionally and independently replaced        by —O—, —S—, —CO—, —CS—, —COCO—, —CONR′—, —CONR′NR′—, —CO₂—,        —OCO—, —NR′CO₂—, —NR′CONR′—, —OCONR′—, —NR′NR′, —NR′NR′CO—,        —NR′CO—, —SO, —SO₂—, —NR′—, —SO₂NR′—, NR′SO₂—, or —NR′SO₂NR′—,        provided that Sp¹ is attached to the carbonyl group through an        atom other than carbon;        ring B¹ is a 4-8 membered, saturated, partially unsaturated, or        aromatic, monocyclic heterocyclic ring having 1-4 heteroatoms        selected from O, S, or N, wherein ring B¹ is optionally        substituted with w₁ independent occurrences of —R¹¹, wherein w₁        is 0-4;        wherein, in ring (B):    -   G₂ is —N—, or CH;    -   each of m₂ and n₂ is independently 0-3, provided that m₂+n₂ is        2-6;    -   p₂ is 0-2; provided that when G₂ is N, then p₂ is not 0;    -   q₂ is 0 or 1;    -   z₂ is 0-4;    -   Sp² is a bond or a C1-C6 alkylidene linker, wherein up to two        methylene units are optionally and independently replaced by        —O—, —S—, —CO—, —CS—, —COCO—, —CONR′—, —CONR′NR′—, —CO₂—, —OCO—,        —NR′CO₂—, —NR′CONR′—, —OCONR′—, —NR′NR′, —NR′NR′CO—, —NR′CO—,        —SO, —SO₂—, —NR′—, —SO₂NR′—, NR′SO₂—, or —NR′SO₂NR′—;    -   ring B² is a 4-8 membered, saturated, partially unsaturated, or        aromatic, monocyclic heterocyclic ring having 1-4 heteroatoms        selected from O, S, or N, wherein ring B is optionally        substituted with w independent occurrences of —R¹², wherein w₂        is 0-4;        wherein, in ring (C) or ring (D):    -   G₃ is —N—, —CH—NH—, or —CH—CH₂—NH—;    -   each of m₃ and n₃ is independently 0-3, provided that m₃+n₃ is        2-6;    -   p₃ is 0-2;    -   z₃ is 0-4;    -   each R^(XX) is hydrogen, C₁₋₆ aliphatic group, a 3-8-membered        saturated, partially unsaturated, or fully unsaturated        monocyclic ring having 0-3 heteroatoms independently selected        from nitrogen, oxygen, or sulfur, or an 8-12 membered saturated,        partially unsaturated, or fully unsaturated bicyclic ring system        having 0-5 heteroatoms independently selected from nitrogen,        oxygen, or sulfur; wherein R^(XX) is optionally substituted with        W₃ independent occurrences of —R¹³, wherein W₃ is 0-3;    -   provided that both R^(XX) are not simultaneously hydrogen;    -   R^(YY) is hydrogen, —COR′, —CO₂R′, —CON(R′)₂, —SOR′, —SO₂R′,        —SO₂N(R′)₂, —COCOR′, —COCH₂COR′, —P(O)(OR′)₂, —P(O)₂OR′, or        —PO(R′);        wherein, in ring (E):    -   each of m₄ and n₄ is independently 0-3, provided that m₄+n₄ is        2-6;    -   p₄ is 1-2;    -   z₄ is 0-4;    -   R^(YZ) is C₁-C₆ aliphatic group, optionally substituted with w₄        independent occurrences of —R¹⁴, wherein w₄ is 0-3;    -   x and y, each, is independently 0-4;    -   W is OR^(XY);    -   R^(XY) is hydrogen or a group selected from:

wherein:

-   -   each of w_(A), w_(B), w_(C), and w_(D) is independently 0 or 1;    -   each M is independently selected from hydrogen, Li, Na, K, Mg,        Ca, Ba, —N(R⁷)₄, C₁-C₁₂-alkyl, C₂-C₁₂-alkenyl, or —R⁶; wherein 1        to 4-CH₂ radicals of the alkyl or alkenyl group, other than the        —CH₂ that is bound to Z, is optionally replaced by a heteroatom        group selected from O, S, S(O), S(O₂), or N(R⁷); and wherein any        hydrogen in said alkyl, alkenyl or R⁶ is optionally replaced        with a substituent selected from oxo, —OR⁷, —R⁷, N(R⁷)₂, N(R⁷)₃,        R⁷OH, —CN, —CO₂R⁷, —C(O)—N(R⁷)₂, S(O)₂—N(R⁷)₂, N(R⁷)—C(O)—R⁷,        C(O)R⁷, —S(O)_(n)—R⁷, OCF₃, —S(O)_(n)—R⁶, N(R⁷)—S(O)₂(R⁷), halo,        —CF₃, or —NO₂;    -   n is 0-2;    -   M′ is H, C₁-C₁₂-alkyl, C₂-C₁₂-alkenyl, or —R⁶; wherein 1 to        4-CH₂ radicals of the alkyl or alkenyl group is optionally        replaced by a heteroatom group selected from O, S, S(O), S(O₂),        or N(R⁷); and wherein any hydrogen in said alkyl, alkenyl or R⁶        is optionally replaced with a substituent selected from oxo,        —OR⁷, —R⁷, —N(R⁷)₂, N(R⁷)₃, —R⁷OH, —CN, —CO₂R⁷, —C(O)—N(R⁷)₂,        —S(O)₂—N(R⁷)₂, —N(R⁷)—C(O)—R⁷, —C(O)R⁷, —S(O)_(n)—R⁷, —OCF₃,        —S(O)_(n)—R⁶, —N(R⁷)—S(O)₂(R⁷), halo, —CF₃, or —NO₂;        -   Z is —CH₂—, —O—, —S—, —N(R⁷)₂—; or,        -   when M is absent, then Z is hydrogen, ═O, or ═S;        -   Y is P or S, wherein when Y is S, then Z is not S;        -   X is O or S;        -   each R⁷ is independently selected from hydrogen, or C₁-C₄            aliphatic, optionally substituted with up to two Q₁;        -   each Q₁ is independently selected from a 3-7 membered            saturated, partially saturated or unsaturated carbocyclic            ring system; or a 5-7 membered saturated, partially            saturated or unsaturated heterocyclic ring containing one or            more heteroatom or heteroatom group selected from O, N, NH,            S, SO, or SO₂; wherein Q, is optionally substituted with up            to three substituents selected from oxo, —OH, —O(C₁-C₄            aliphatic), —C₁-C₄ aliphatic, —NH₂, NH(C₁-C₄ aliphatic),            —N(C₁-C₄ aliphatic)₂, —N(C₁-C₄ aliphatic)-C(O)—C₁-C₄            aliphatic, —(C₁-C₄ aliphatic)-OH, —CN, —CO₂H, —CO₂(C₁-C₄            aliphatic), —C(O)—NH₂, —C(O)—NH(C₁-C₄ aliphatic),            —C(O)—N(C₁-C₄ aliphatic)₂, halo or —CF₃;        -   R⁶ is a 5-6 membered saturated, partially saturated or            unsaturated carbocyclic or heterocyclic ring system, or an            8-10 membered saturated, partially saturated or unsaturated            bicyclic ring system; wherein any of said heterocyclic ring            systems contains one or more heteroatoms selected from O, N,            S, S(O)_(n) or N(R⁷); and wherein any of said ring systems            optionally contains 1 to 4 substituents independently            selected from OH, C₁-C₄ alkyl, O—C₁-C₄ alkyl or O—C(O)—C₁-C₄            alkyl;        -   R⁹ is C(R⁷)₂, O or N(R⁷);        -   each occurrence of R¹¹, R¹², R¹³, R¹⁴, R³, R⁴, and R⁵ is            independently Q-R^(X); wherein Q is a bond or is a C₁-C₆            alkylidene chain wherein up to two non-adjacent methylene            units of Q are optionally and independently replaced by            —NR—, —S—, —O—, —CS—, —CO₂—, —OCO—, —CO—, —COCO—, —CONR—,            —NRCO—, —NRCO₂—, —SO₂NR—, —NRSO₂—, —CONRNR—, —NRCONR—,            —OCONR—, —NRNR—, —NRSO₂NR—, —SO—, —SO₂—, —PO—, —PO₂—,            —OP(O)(OR)—, or —POR—; and each occurrence of R^(X) is            independently selected from —R′, halogen, ═O, ═NR′, —NO₂,            —CN, —OR′, —SR′, —N(R′)₂, —NR′COR′, —NR′CON(R′)₂, —NR′CO₂R′,            —COR′, —CO₂R′, —OCOR′, —CON(R′)₂, —OCON(R′)₂, —SOR′, —SO₂R′,            —SO₂N(R′)₂, —NR′SO₂R′, —NR′SO₂N(R′)₂, —COCOR′, —COCH₂COR′,            —OP(O)(OR′)₂, —P(O)(OR′)₂, —OP(O)₂OR′, —P(O)₂OR′, —PO(R′)₂,            or —OPO(R′)₂; and        -   each occurrence of R is independently hydrogen or C₁₋₆            aliphatic group having up to three substituents; and each            occurrence of R is independently hydrogen or C₁₋₆ aliphatic            group, a 3-8-membered saturated, partially unsaturated, or            fully unsaturated monocyclic ring having 0-3 heteroatoms            independently selected from nitrogen, oxygen, or sulfur, or            an 8-12 membered saturated, partially unsaturated, or fully            unsaturated bicyclic ring system having 0-5 heteroatoms            independently selected from nitrogen, oxygen, or sulfur,            wherein R′ has up to four substituents; or R and R′, two            occurrences of R, or two occurrences of R′, are taken            together with the atom(s) to which they are bound to form an            optionally substituted 3-12 membered saturated, partially            unsaturated, or fully unsaturated monocyclic or bicyclic            ring having 0-4 heteroatoms independently selected from            nitrogen, oxygen, or sulfur.

2. Compounds and Definitions

Compounds of this invention include those described generally above, andare further illustrated by the classes, subclasses, and speciesdisclosed herein. As used herein, the following definitions shall applyunless otherwise indicated. For purposes of this invention, the chemicalelements are identified in accordance with the Periodic Table of theElements, CAS version, Handbook of Chemistry and Physics, 75^(th) Ed.Additionally, general principles of organic chemistry are described in“Organic Chemistry”, Thomas Sorrell, University Science Books,Sausalito: 1999, and “March's Advanced Organic Chemistry”, 5^(th) Ed.,Ed.: Smith, M. B. and March, J., John Wiley & Sons, New York: 2001, theentire contents of which are hereby incorporated by reference.

As described herein, compounds of the invention may optionally besubstituted with one or more substituents, such as are illustratedgenerally above, or as exemplified by particular classes, subclasses,and species of the invention. It will be appreciated that the phrase“optionally substituted” is used interchangeably with the phrase“substituted or unsubstituted.” In general, the term “substituted”,whether preceded by the term “optionally” or not, refers to thereplacement of hydrogen radicals in a given structure with the radicalof a specified substituent. Unless otherwise indicated, an optionallysubstituted group may have a substituent at each substitutable positionof the group, and when more than one position in any given structure maybe substituted with more than one substituent selected from a specifiedgroup, the substituent may be either the same or different at everyposition. Combinations of substituents envisioned by this invention arepreferably those that result in the formation of stable or chemicallyfeasible compounds. The term “stable”, as used herein, refers tocompounds that are not substantially altered when subjected toconditions to allow for their production, detection, and preferablytheir recovery, purification, and use for one or more of the purposesdisclosed herein. In some embodiments, a stable compound or chemicallyfeasible compound is one that is not substantially altered when kept ata temperature of 40° C. or less, in the absence of moisture or otherchemically reactive conditions, for at least a week.

The term “aliphatic” or “aliphatic group”, as used herein, means astraight-chain (i.e., unbranched) or branched, substituted orunsubstituted hydrocarbon chain that is completely saturated or thatcontains one or more units of unsaturation, or a monocyclic hydrocarbonor bicyclic hydrocarbon that is completely saturated or that containsone or more units of unsaturation, but which is not aromatic (alsoreferred to herein as “carbocycle” “cycloaliphatic” or “cycloalkyl”),that has a single point of attachment to the rest of the molecule.Unless otherwise specified, aliphatic groups contain 1-20 aliphaticcarbon atoms. In some embodiments, aliphatic groups contain 1-10aliphatic carbon atoms. In other embodiments, aliphatic groups contain1-8 aliphatic carbon atoms. In still other embodiments, aliphatic groupscontain 1-6 aliphatic carbon atoms, and in yet other embodimentsaliphatic groups contain 1-4 aliphatic carbon atoms. In someembodiments, “cycloaliphatic” (or “carbocycle” or “cycloalkyl”) refersto a monocyclic C₃-C₈ hydrocarbon or bicyclic C₈-C₁₂ hydrocarbon that iscompletely saturated or that contains one or more units of unsaturation,but which is not aromatic, that has a single point of attachment to therest of the molecule wherein any individual ring in said bicyclic ringsystem has 3-7 members. Suitable aliphatic groups include, but are notlimited to, linear or branched, substituted or unsubstituted alkyl,alkenyl, alkynyl groups and hybrids thereof such as (cycloalkyl)alkyl,(cycloalkenyl)alkyl or (cycloalkyl)alkenyl.

The term “heteroaliphatic”, as used herein, means aliphatic groupswherein one or two carbon atoms are independently replaced by one ormore of oxygen, sulfur, nitrogen, phosphorus, or silicon.Heteroaliphatic groups may be substituted or unsubstituted, branched orunbranched, cyclic or acyclic, and include “heterocycle”,“heterocyclyl”, “heterocycloaliphatic”, or “heterocyclic” groups.

The term “heterocycle”, “heterocyclyl”, “heterocycloaliphatic”, or“heterocyclic” as used herein means non-aromatic, monocyclic, bicyclic,or tricyclic ring systems in which one or more ring members are anindependently selected heteroatom. In some embodiments, the“heterocycle”, “heterocyclyl”, “heterocycloaliphatic”, or “heterocyclic”group has three to fourteen ring members in which one or more ringmembers is a heteroatom independently selected from oxygen, sulfur,nitrogen, or phosphorus, and each ring in the system contains 3 to 7ring members.

The term “heteroatom” means one or more of oxygen, sulfur, nitrogen,phosphorus, or silicon (including, any oxidized form of nitrogen,sulfur, phosphorus, or silicon; the quaternized form of any basicnitrogen or; a substitutable nitrogen of a heterocyclic ring, forexample N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) orNR⁺ (as in N-substituted pyrrolidinyl)).

The term “unsaturated”, as used herein, means that a moiety has one ormore units of unsaturation.

The term “alkoxy”, or “thioalkyl”, as used herein, refers to an alkylgroup, as previously defined, attached to the principal carbon chainthrough an oxygen (“alkoxy”) or sulfur (“thioalkyl”) atom.

The terms “haloalkyl”, “haloalkenyl” and “haloalkoxy” means alkyl,alkenyl or alkoxy, as the case may be, substituted with one or morehalogen atoms. The term “halogen” means F, Cl, Br, or I.

The term “aryl” used alone or as part of a larger moiety as in“aralkyl”, “aralkoxy”, or “aryloxyalkyl”, refers to monocyclic,bicyclic, and tricyclic ring systems having a total of five to fourteenring members, wherein at least one ring in the system is aromatic andwherein each ring in the system contains 3 to 7 ring members. The term“aryl” may be used interchangeably with the term “aryl ring”. The term“aryl” also refers to heteroaryl ring systems as defined hereinbelow.

The term “heteroaryl”, used alone or as part of a larger moiety as in“heteroaralkyl” or “heteroarylalkoxy”, refers to monocyclic, bicyclic,and tricyclic ring systems having a total of five to fourteen ringmembers, wherein at least one ring in the system is aromatic, at leastone ring in the system contains one or more heteroatoms, and whereineach ring in the system contains 3 to 7 ring members. The term“heteroaryl” may be used interchangeably with the term “heteroaryl ring”or the term “heteroaromatic”.

An aryl (including aralkyl, aralkoxy, aryloxyalkyl and the like) orheteroaryl (including heteroaralkyl and heteroarylalkoxy and the like)group may contain one or more substituents and thus may be “optionallysubstituted”. Unless otherwise defined above and herein, suitablesubstituents on the unsaturated carbon atom of an aryl or heteroarylgroup are generally selected from halogen; —R^(o); —OR^(o); —SR^(o);phenyl (Ph) optionally substituted with R^(o); —O(Ph) optionallysubstituted with R^(o); —(CH₂)₁₋₂(Ph), optionally substituted withR^(o); —CH═CH(Ph), optionally substituted with R^(o); —NO₂; —CN;—N(R^(o))₂; —NR^(o)C(O)R^(o); —NR^(o)C(S)R^(o); —NR^(o)C(O)N(R^(o))₂;—NR^(o)C(S)N(R^(o))₂; —NR^(o)CO₂R^(o); —NR^(o)NR^(o)C(O)R^(o);—NR^(o)NR^(o)C(O)N(R^(o))₂; —NR^(o)NR^(o)CO₂R^(o); —C(O)C(O)R^(o);—C(O)CH₂C(O)R^(o); —CO₂R^(o); —C(O)R^(o); —C(S)R^(o); —C(O)N(R^(o))₂;—C(S)N(R^(o))₂; —OC(O)N(R^(o))₂; —OC(O)R^(o); —C(O)N(OR^(o))R^(o);—C(NOR^(o))R^(o); —S(O)₂R^(o); —S(O)₃R^(o); —SO₂N(R^(o))₂; —S(O)R^(o);—NR^(o)SO₂N(R^(o))₂; —NR^(o)SO₂R^(o); —N(OR^(o))R^(o);—C(═NH)—N(R^(o))₂; —P(O)₂R^(o); —PO(R^(o))₂; —OPO(R^(o))₂;—(CH₂)₀₋₂NHC(O)R^(o); phenyl (Ph) optionally substituted with R^(o);—O(Ph) optionally substituted with R^(o); —(CH₂)₁₋₂(Ph), optionallysubstituted with R^(o); or —CH═CH(Ph), optionally substituted withR^(o); wherein each independent occurrence of R^(o) is selected fromhydrogen, optionally substituted C₁₋₆ aliphatic, an unsubstituted 5-6membered heteroaryl or heterocyclic ring, phenyl, —O(Ph), or —CH₂(Ph),or, notwithstanding the definition above, two independent occurrences ofR^(o), on the same substituent or different substituents, taken togetherwith the atom(s) to which each R^(o) group is bound, to form anoptionally substituted 3-12 membered saturated, partially unsaturated,or fully unsaturated monocyclic or bicyclic ring having 0-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur.

Optional substituents on the aliphatic group of R^(o) are selected fromNH₂, NH(C₁₋₄aliphatic), N(C₁₋₄aliphatic)₂, halogen, C₁₋₄aliphatic, OH,O(C₁₋₄aliphatic), NO₂, CN, CO₂H, CO₂(C₁₋₄aliphatic), O(haloC₁₋₄aliphatic), or haloC₁₋₄aliphatic, wherein each of the foregoingC₁₋₄aliphatic groups of R^(o) is unsubstituted.

An aliphatic or heteroaliphatic group, or a non-aromatic heterocyclicring may contain one or more substituents and thus may be “optionallysubstituted”. Unless otherwise defined above and herein, suitablesubstituents on the saturated carbon of an aliphatic or heteroaliphaticgroup, or of a non-aromatic heterocyclic ring are selected from thoselisted above for the unsaturated carbon of an aryl or heteroaryl groupand additionally include the following: ═O, ═S, ═NNHR*, ═NN(R*)₂,═NNHC(O)R*, ═NNHCO₂(alkyl), ═NNHSO₂(alkyl), or ═NR*, where each R* isindependently selected from hydrogen or an optionally substituted C₁₋₆aliphatic group.

Unless otherwise defined above and herein, optional substituents on thenitrogen of a non-aromatic heterocyclic ring are generally selected from—R⁺, —N(R⁺)₂, —C(O)R⁺, —CO₂R⁺, —C(O)C(O)R⁺, —C(O)CH₂C(O)R⁺, —SO₂R⁺,—SO₂N(R⁺)₂, —C(═S)N(R⁺)₂, —C(═NH)—N(R⁺)₂, or —NR⁺SO₂R⁺; wherein R⁺ ishydrogen, an optionally substituted C₁₋₆ aliphatic, optionallysubstituted phenyl, optionally substituted —O(Ph), optionallysubstituted —CH₂(Ph), optionally substituted —(CH₂)₁₋₂(Ph); optionallysubstituted —CH═CH(Ph); or an unsubstituted 5-6 membered heteroaryl orheterocyclic ring having one to four heteroatoms independently selectedfrom oxygen, nitrogen, or sulfur, or, notwithstanding the definitionabove, two independent occurrences of R⁺, on the same substituent ordifferent substituents, taken together with the atom(s) to which each R⁺group is bound, form an optionally substituted 3-12 membered saturated,partially unsaturated, or fully unsaturated monocyclic or bicyclic ringhaving 0-4 heteroatoms independently selected from nitrogen, oxygen, orsulfur.

Optional substituents on the aliphatic group or the phenyl ring of R⁺are selected from —NH₂, —NH(C₁₋₄ aliphatic), —N(C₁₋₄ aliphatic)₂,halogen, C₁₋₄ aliphatic, —OH, —O(C₁₋₄ aliphatic), —NO₂, —CN, —CO₂H,—CO₂(C₁₋₄ aliphatic), —O(halo C₁₋₄ aliphatic), or halo(C₁₋₄ aliphatic),wherein each of the foregoing C₁₋₄aliphatic groups of R⁺ isunsubstituted.

The term “alkylidene chain” refers to a straight or branched carbonchain that may be fully saturated or have one or more units ofunsaturation and has two points of attachment to the rest of themolecule.

As detailed above, in some embodiments, two independent occurrences ofR^(o) (or R⁺, R, R′ or any other variable similarly defined herein), aretaken together with the atom(s) to which they are bound to form anoptionally substituted 3-12 membered saturated, partially unsaturated,or fully unsaturated monocyclic or bicyclic ring having 0-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur.

Exemplary rings that are formed when two independent occurrences ofR^(o) (or R⁺, R, R′ or any other variable similarly defined herein), aretaken together with the atom(s) to which each variable is bound include,but are not limited to the following: a) two independent occurrences ofR^(o) (or R⁺, R, R′ or any other variable similarly defined herein) thatare bound to the same atom and are taken together with that atom to forma ring, for example, N(R^(o))₂, where both occurrences of R^(o) aretaken together with the nitrogen atom to form a piperidin-1-yl,piperazin-1-yl, or morpholin-4-yl group; and b) two independentoccurrences of R^(o) (or R⁺, R, R′ or any other variable similarlydefined herein) that are bound to different atoms and are taken togetherwith both of those atoms to form a ring, for example where a phenylgroup is substituted with two occurrences of OR^(o)

these two occurrences of R^(o) are taken together with the oxygen atomsto which they are bound to form a fused 6-membered oxygen containingring:

It will be appreciated that a variety of other rings can be formed whentwo independent occurrences of R^(o) (or R⁺, R, R′ or any other variablesimilarly defined herein) are taken together with the atom(s) to whicheach variable is bound and that the examples detailed above are notintended to be limiting.

Unless otherwise stated, structures depicted herein are also meant toinclude all isomeric (e.g., enantiomeric, diastereomeric, and geometric(or conformational)) forms of the structure; for example, the R and Sconfigurations for each asymmetric center, (Z) and (E) double bondisomers, and (Z) and (E) conformational isomers. Therefore, singlestereochemical isomers as well as enantiomeric, diastereomeric, andgeometric (or conformational) mixtures of the present compounds arewithin the scope of the invention. Unless otherwise stated, alltautomeric forms of the compounds of the invention are within the scopeof the invention. Additionally, unless otherwise stated, structuresdepicted herein are also meant to include compounds that differ only inthe presence of one or more isotopically enriched atoms. For example,compounds having the present structures except for the replacement ofhydrogen by deuterium or tritium, or the replacement of a carbon by a¹³C- or ¹⁴C-enriched carbon are within the scope of this invention. Suchcompounds are useful, for example, as analytical tools or probes inbiological assays.

3. Description of Exemplary Compounds

In one embodiment, R is hydrogen. Or, R is C1-C6 aliphatic. Exemplary Rincludes C1-C6 alkyl, e.g., methyl, ethyl, propyl, or butyl.

In one embodiment, R′ is hydrogen.

In one embodiment, R′ is a C1-C8 aliphatic group, optionally substitutedwith up to 3 substituents selected from halo, CN, CF₃, CHF₂, OCF₃, orOCHF₂, wherein up to two methylene units of said C1-C8 aliphatic isoptionally replaced with —CO—, —CONH(C1-C4 alkyl)-, —CO₂—, —OCO—,—N(C1-C4 alkyl)CO₂—, —O—, —N(C1-C4 alkyl)CON(C1-C4 alkyl)-, —OCON(C1-C4alkyl)-, —N(C1-C4 alkyl)CO—, —S—, —N(C1-C4 alkyl)-, —SO₂N(C1-C4 alkyl)-,N(C1-C4 alkyl)SO₂—, or —N(C1-C4 alkyl)SO₂N(C1-C4 alkyl)-.

In one embodiment, R′ is a 3-8 membered saturated, partiallyunsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, wherein R′ isoptionally substituted with up to 3 substituents selected from halo, CN,CF₃, CHF₂, OCF₃, OCHF₂, or C1-C6 alkyl, wherein up to two methyleneunits of said C1-C6 alkyl is optionally replaced with —CO—, —CONH(C1-C4alkyl)-, —CO₂—, —OCO—, —N(C1-C4 alkyl)CO₂—, —O—, —N(C1-C4alkyl)CON(C1-C4 alkyl)-, —OCON(C1-C4 alkyl)-, —N(C1-C4 alkyl)CO—, —S—,—N(C1-C4 alkyl)-, —SO₂N(C1-C4 alkyl)-, N(C1-C4 alkyl)SO₂—, or —N(C1-C4alkyl)SO₂N(C1-C4 alkyl)-.

In one embodiment, R′ is an 8-12 membered saturated, partiallyunsaturated, or fully unsaturated bicyclic ring system having 0-5heteroatoms independently selected from nitrogen, oxygen, or sulfur;wherein R′ is optionally substituted with up to 3 substituents selectedfrom halo, CN, CF₃, CHF₂, OCF₃, OCHF₂, or C1-C6 alkyl, wherein up to twomethylene units of said C1-C6 alkyl is optionally replaced with —CO—,—CONH(C1-C4 alkyl)-, —CO₂—, —OCO—, —N(C1-C4 alkyl)CO₂—, —O—, —N(C1-C4alkyl)CON(C1-C4 alkyl)-, —OCON(C1-C4 alkyl)-, —N(C1-C4 alkyl)CO—, —S—,—N(C1-C4 alkyl)-, —SO₂N(C1-C4 alkyl)-, N(C1-C4 alkyl)SO₂—, or —N(C1-C4alkyl)SO₂N(C1-C4 alkyl)-.

In one embodiment, two occurrences of R′ are taken together with theatom(s) to which they are bound to form an optionally substituted 3-12membered saturated, partially unsaturated, or fully unsaturatedmonocyclic or bicyclic ring having 0-4 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur, wherein R′ is optionallysubstituted with up to 3 substituents selected from halo, CN, CF₃, CHF₂,OCF₃, OCHF₂, or C1-C6 alkyl, wherein up to two methylene units of saidC1-C6 alkyl is optionally replaced with —CO—, —CONH(C1-C4 alkyl)-,—CO₂—, —OCO—, —N(C1-C4 alkyl)CO₂—, —O—, —N(C1-C4 alkyl)CON(C1-C4alkyl)-, —OCON(C1-C4 alkyl)-, —N(C1-C4 alkyl)CO—, —S—, —N(C1-C4 alkyl)-,—SO₂N(C1-C4 alkyl)-, N(C1-C4 alkyl)SO₂—, or —N(C1-C4 alkyl)SO₂N(C1-C4alkyl)-.

In another embodiment, W is OH.

In still another embodiment, R^(XY) is:

In certain embodiment, Y is P and X is O.

In another embodiment, each Z is —O—.

In yet another embodiment, R^(XY) is selected from:

In yet another embodiment, R^(XY) is selected from:

-(L)-lysine, —PO₃Na₂,

-(L)-tyrosine,

—PO₃Mg, —PO₃(NH₄)₂, —CH₂—OPO₃Na₂,

-(L)-serine, —SO₃Na₂,

—SO₃Mg, —SO₃(NH₄)₂, —CH₂—OSO₃Na₂, —CH₂—OSO₃(NH₄)₂,

acetyl,

-(L)-valine, -(L)-glutamic acid, -(L)-aspartic acid,-(L)-γ-t-butyl-aspartic acid,

-(L)-3-pyridylalanine, -(L)-histidine,

PO₃K₂, PO₃Ca, PO₃-spermine, PO₃-(spermidine)₂ or PO₃-(meglamine)₂.

In yet another embodiment, R^(XY) is selected from:

R^(XY)

—SO₃H —SO₃H

PO₃K₂ PO₃Ca PO₃Mg

In one embodiment, x is 0-2. Or, x is 1 or 2. Or, x is 1.

In one embodiment, R³ is present at the 6- or 7-position of thequinazoline ring.

In another embodiment, R³ is selected from halo, CN, NO₂, —N(R′)₂,—CH₂N(R′)₂, —OR′, —CH₂OR′, —SR′, —CH₂SR′, —COOR′, —NRCOR′, —CON(R′)₂,—OCON(R′)₂, COR′, —NHCOOR′, —SO₂R′, —SO₂N(R′)₂, or an optionallysubstituted group selected from C₁-C₆aliphatic, aryl, heteroaryl,cycloaliphatic, heterocycloaliphatic, arylC₁-C₆alkyl,heteroarylC₁-C₆alkyl, cycloaliphaticC₁-C₆alkyl, orheterocycloaliphaticC₁-C₆alkyl.

In one embodiment, R³ is independently Cl, Br, F, CF₃, —OCF₃, Me, Et,CN, —COOH, —NH₂, —N(CH₃)₂, —N(Et)₂, —N(iPr)₂, —O(CH₂)₂OCH₃, —CONH₂,—COOCH₃, —OH, —OCH₃, —OCH₂CH₃, —CH₂OH, —NHCOCH₃, —NHCOCH(CH₃)₂, —SO₂NH₂,—CONH(cyclopropyl), —CONHCH₃, —CONHCH₂CH₃, or an optionally substitutedgroup selected from -piperidinyl, piperizinyl, morpholino, phenyl,phenyloxy, benzyl, or benzyloxy.

In another embodiment, each R³ group is independently halogen, CN,optionally substituted C₁-C₆alkyl, OR′, N(R′)₂, CON(R′)₂, or NRCOR′.

In one embodiment, x is 1 or 2, and each R³ group is —Cl, —CH₃, —CH₂CH₃,—F, —CF₃, —OCF₃, —CONHCH₃, —CONHCH₂CH₃, —CONH(cyclopropyl), —OCH₃, —NH₂,—OCH₂CH₃, or —CN.

In yet another embodiment, x is 1 and R³ is at the 6-position of thequinazoline ring and is selected from —Cl, —CH₃, —CH₂CH₃, —F, —CF₃,—OCF₃, —CONHCH₃, —CONHCH₂CH₃, —CONH(cyclopropyl), —OCH₃, —NH₂, —OCH₂CH₃,or —CN.

In yet another embodiment, x is 1 and R³ is at the 6-position of thequinazoline ring and is —Cl, —CH₃, —CH₂CH₃, —F, —CF₃, —OCF₃, —OCH₃, or—OCH₂CH₃.

In one embodiment, R³ is at the 6-position of the quinazoline ring andis —CON(R′)₂, or NRCOR′.

In another embodiment, x is 1 and R³ is at the 7-position of thequinazoline ring and is selected from —Cl, —CH₃, —CH₂CH₃, —F, —CF₃,—OCF₃, —CONHCH₃, —CONHCH₂CH₃, —CONH(cyclopropyl), —OCH₃, —NH₂, —OCH₂CH₃,or —CN.

In yet another embodiment, x is 1 and R³ is at the 7-position of thequinazoline ring and is —Cl, —CH₃, —CH₂CH₃, —F, —CF₃, —OCF₃, —OCH₃, or—OCH₂CH₃. Or, x is 1 and R³ is at the 7-position of the quinazoline ringand is —CON(R′)₂, or NRCOR′.

In one embodiment, y is 0-4 and R⁵ is independently halogen, CN, NO₂,—N(R′)₂, —CH₂N(R′)₂, —OR′, —CH₂OR′, —SR′, —CH₂SR′, —NRCOR′, —CON(R′)₂,—S(O)₂N(R′)₂, —OCOR′, —COR′, —CO₂R′, —OCON(R′)₂, —NR′SO₂R′,—OP(O)(OR′)₂, —P(O)(OR′)₂, —OP(O)₂OR′, —P(O)₂OR′, —PO(R′)₂, —OPO(R′)₂,or an optionally substituted group selected from C₁-C₆aliphatic, aryl,heteroaryl, cycloaliphatic, heterocycloaliphatic, arylC₁-C₆alkyl,heteroarylC₁-C₆alkyl, cycloaliphaticC₁-C₆alkyl, orheterocycloaliphaticC₁-C₆alkyl.

In another embodiment, R⁵ is independently Cl, Br, F, CF₃, Me, Et, CN,—COOH, —NH₂, —N(CH₃)₂, —N(Et)₂, —N(iPr)₂, —O(CH₂)₂OCH₃, —CONH₂, —COOCH₃,—OH, —OCH₃, —OCH₂CH₃, —CH₂OH, —NHCOCH₃, —SO₂NH₂, —SO₂NHC(CH₃)₂,—OCOC(CH₃)₃, —OCOCH₂C(CH₃)₃, —O(CH₂)₂N(CH₃)₂, 4-CH₃-piperazin-1-yl,OCOCH(CH₃)₂, OCO(cyclopentyl), —COCH₃, optionally substituted phenoxy,or optionally substituted benzyloxy.

In certain embodiments, each of z₁, z₂, z₃, or z₄ is independently 0-2.In other embodiments, each of z₁, z₂, z₃, or z₄ is 0 and the ring isunsubstituted. Preferred R⁴ groups, when present, are each independentlyhalogen, CN, NO₂, —N(R′)₂, —CH₂N(R′)₂, —OR′, —CH₂OR′, —SR′, —CH₂SR′,—COOR′, —NRCOR′, —CON(R′)₂, —OCON(R′)₂, COR′, —NHCOOR′, —SO₂R′,—SO₂N(R′)₂, or an optionally substituted group selected fromC₁-C₆aliphatic, aryl, heteroaryl, cycloaliphatic, heterocycloaliphatic,arylC₁-C₆alkyl, heteroarylC₁-C₆alkyl, cycloaliphaticC₁-C₆alkyl, orheterocycloaliphatic C₁-C₆alkyl. Other exemplary R⁴ groups are Cl, Br,F, CF₃, CH₃, —CH₂CH₃, CN, —COOH, —N(CH₃)₂, —N(Et)₂, —N(iPr)₂,—O(CH₂)₂OCH₃, —CONH₂, —COOCH₃, —OH, —CH₂OH, —NHCOCH₃, —SO₂NH₂,—SO₂(CH₂)₃CH₃, —SO₂CH(CH₃)₂, —SO₂N(CH₃)₂, —SO₂CH₂CH₃, —C(O)OCH₂CH(CH₃)₂,—C(O)NHCH₂CH(CH₃)₂, —NHCOOCH₃, —C(O)C(CH₃)₃, —COO(CH₂)₂CH₃,—C(O)NHCH(CH₃)₂, —C(O)CH₂CH₃, or an optionally substituted groupselected from piperidinyl, piperizinyl, morpholino, C₁₋₄alkoxy, phenyl,phenyloxy, benzyl, benzyloxy, —CH₂cyclohexyl, pyridyl, —CH₂pyridyl, or—CH₂thiazolyl

In certain embodiments, x is 0-2. In other embodiments, x is 1 or 2. Instill other embodiments x is 1 and R³ is substituted at the 6- or7-position of the quinazoline ring. When the quinazoline ring issubstituted (x is 1-4), R³ groups are halogen, CN, NO₂, —N(R′)₂,—CH₂N(R′)₂, —OR′, —CH₂OR′, —SR′, —CH₂SR′, —COOR′, —NRCOR′, —CON(R′)₂,—OCON(R′)₂, COR′, —NHCOOR′, —SO₂R′, —SO₂N(R′)₂, or an optionallysubstituted group selected from C₁-C₆aliphatic, aryl, heteroaryl,cycloaliphatic, heterocycloaliphatic, arylC₁-C₆alkyl,heteroarylC₁-C₆alkyl, cycloaliphaticC₁-C₆alkyl, orheterocycloaliphaticC₁-C₆alkyl. In still other embodiments, eachoccurrence of R³ is independently Cl, Br, F, CF₃, —OCF₃, Me, Et, CN,—COOH, —NH₂, —N(CH₃)₂, —N(Et)₂, —N(iPr)₂, —O(CH₂)₂OCH₃, —CONH₂, —COOCH₃,—OH, —OCH₃, —OCH₂CH₃, —CH₂OH, —NHCOCH₃, —NHCOCH(CH₃)₂, —SO₂NH₂,—CONH(cyclopropyl), —CONHCH₃, —CONHCH₂CH₃, or an optionally substitutedgroup selected from -piperidinyl, piperizinyl, morpholino, phenyl,phenyloxy, benzyl, or benzyloxy. In still other embodiments, x is 1 or 2and each R³ group is independently halogen, CN, optionally substitutedC₁-C₆alkyl, OR′, N(R′)₂, CON(R′)₂, or NRCOR′. In yet other embodiments,x is 1 or 2, and each R³ group is —Cl, —CH₃, —CH₂CH₃, —F, —CF₃, —OCF₃,—CONHCH₃, —CONHCH₂CH₃, —CONH(cyclopropyl), —OCH₃, —NH₂, —OCH₂CH₃, or—CN. In still other embodiments, x is 1 and R³ is at the 6-position ofthe quinazoline ring and is —Cl, —CH₃, —CH₂CH₃, —F, —CF₃, —OCF₃,—CONHCH₃, —CONHCH₂CH₃, —CONH(cyclopropyl), —OCH₃, —NH₂, —OCH₂CH₃, or—CN. IN yet other embodiments, x is 1 and R³ is at the 7-position of thequinazoline ring and is —Cl, —CH₃, —CH₂CH₃, —F, —CF₃, —OCF₃, —CONHCH₃,—CONHCH₂CH₃, —CONH(cyclopropyl), —OCH₃, —NH₂, —OCH₂CH₃, or —CN. In otherembodiments, x is 1 and R³ is at the 6-position of the quinazoline ringand is —Cl, —CH₃, —CH₂CH₃, —F, —CF₃, —OCF₃, —OCH₃, or —OCH₂CH₃. In stillother embodiments, x is 1 and R³ is at the 7-position of the quinazolinering and is —Cl, —CH₃, —CH₂CH₃, —F, —CF₃, —OCF₃, —OCH₃, or —OCH₂CH₃. Inother embodiments, x is 1 and R³ is at the 6-position of the quinazolinering and is —CON(R′)₂, or NRCOR′. In yet other embodiments, x is 1 andR³ is at the 7-position of the quinazoline ring and is —CON(R′)₂, orNRCOR′.

In some embodiments, y is 0-4 and R⁵ group, when present, is eachindependently halogen, CN, NO₂, —N(R′)₂, —CH₂N(R′)₂, —OR′, —CH₂OR′,—SR′, —CH₂SR′, —NRCOR′, —CON(R′)₂, —S(O)₂N(R′)₂, —OCOR′, —COR′, —CO₂R′,—OCON(R′)₂, —NR′SO₂R′, —OP(O)(OR′)₂, —P(O)(OR′)₂, —OP(O)₂OR′, —P(O)₂OR′,—PO(R′)₂, —OPO(R′)₂, or an optionally substituted group selected fromC₁-C₆aliphatic, aryl, heteroaryl, cycloaliphatic, heterocycloaliphatic,arylC₁-C₆alkyl, heteroarylC₁-C₆alkyl, cycloaliphaticC₁-C₆alkyl, orheterocycloaliphaticC₁-C₆alkyl.

In yet other embodiments, y is 0-4 and each occurrence of R⁵ isindependently Cl, Br, F, CF₃, Me, Et, CN, —COOH, —NH₂, —N(CH₃)₂,—N(Et)₂, —N(iPr)₂, —O(CH₂)₂OCH₃, —CONH₂, —COOCH₃, —OH, —OCH₃, —OCH₂CH₃,—CH₂OH, —NHCOCH₃, —SO₂NH₂, —SO₂NHC(CH₃)₂, —OCOC(CH₃)₃, —OCOCH₂C(CH₃)₃,—O(CH₂)₂N(CH₃)₂, 4-CH₃-piperazin-1-yl, OCOCH(CH₃)₂, OCO(cyclopentyl),—COCH₃, optionally substituted phenoxy, or optionally substitutedbenzyloxy.

In yet another embodiment, each of z₁, z₂, z₃, or z₄ is 0-4, and R⁴groups, when present, are each independently halogen, CN, NO₂, —N(R′)₂,—CH₂N(R′)₂, —OR′, —CH₂OR′, —SR′, —CH₂SR′, —COOR′, —NRCOR′, —CON(R′)₂,—OCON(R′)₂, COR′, —NHCOOR′, —SO₂R′, —SO₂N(R′)₂, or an optionallysubstituted group selected from C₁-C₆aliphatic, aryl, heteroaryl,cycloaliphatic, heterocycloaliphatic, arylC₁-C₆alkyl,heteroarylC₁-C₆alkyl, cycloaliphaticC₁-C₆alkyl, orheterocycloaliphaticC₁-C₆alkyl.

In still other embodiments, each of z₁, z₂, z₃, or z₄ is 0-4 and R⁴groups are each independently Cl, Br, F, CF₃, CH₃, —CH₂CH₃, CN, —COOH,—N(CH₃)₂, —N(Et)₂, —N(iPr)₂, —O(CH₂)₂OCH₃, —CONH₂, —COOCH₃, —OH, —CH₂OH,—NHCOCH₃, —SO₂NH₂, —SO₂(CH₂)₃CH₃, —SO₂CH(CH₃)₂, —SO₂N(CH₃)₂, —SO₂CH₂CH₃,—C(O)OCH₂CH(CH₃)₂, —C(O)NHCH₂CH(CH₃)₂, —NHCOOCH₃, —C(O)C(CH₃)₃,—COO(CH₂)₂CH₃, —C(O)NHCH(CH₃)₂, —C(O)CH₂CH₃, or an optionallysubstituted group selected from -piperidinyl, piperizinyl, morpholino,C₁₋₄alkoxy, phenyl, phenyloxy, benzyl, benzyloxy, —CH₂cyclohexyl,pyridyl, —CH₂pyridyl, or —CH₂thiazolyl.

For compounds described directly above, in some embodiments, x is 0-4,and R³ groups, when present, are each independently halogen, CN, NO₂,—N(R′)₂, —CH₂N(R′)₂, —OR′, —CH₂OR′, —SR′, —CH₂SR′, —COOR′, —NRCOR′,—CON(R′)₂, —OCON(R′)₂, COR′, —NHCOOR′, —SO₂R′, —SO₂N(R′)₂, or anoptionally substituted group selected from C₁-C₆aliphatic, aryl,heteroaryl, cycloaliphatic, heterocycloaliphatic, arylC₁-C₆alkyl,heteroarylC₁-C₆alkyl, cycloaliphaticC₁-C₆alkyl, orheterocycloaliphaticC₁-C₆alkyl.

In yet other embodiments, x is 1 or 2, and each occurrence of R³ isindependently Cl, Br, F, CF₃, —OCF₃, Me, Et, CN, —COOH, —NH₂, —N(CH₃)₂,—N(Et)₂, —N(iPr)₂, —O(CH₂)₂OCH₃, —CONH₂, —COOCH₃, —OH, —OCH₃, —OCH₂CH₃,—CH₂OH, —NHCOCH₃, —NHCOCH(CH₃)₂, —SO₂NH₂, —CONH(cyclopropyl), —CONHCH₃,—CONHCH₂CH₃, or an optionally substituted group selected from-piperidinyl, piperizinyl, morpholino, phenyl, phenyloxy, benzyl, orbenzyloxy.

In still other embodiments, x is 1 or 2 and each R³ group isindependently halogen, CN, optionally substituted C₁-C₆alkyl, OR′,N(R′)₂, CON(R′)₂, or NRCOR′.

In yet other embodiments, x is 1 or 2, and each R³ group is —Cl, —CH₃,—CH₂CH₃, —F, —CF₃, —OCF₃, —CONHCH₃, —CONHCH₂CH₃, —CONH(cyclopropyl),—OCH₃, —NH₂, —OCH₂CH₃, or —CN.

In still other embodiments, x is 1 and R³ is at the 6-position of thequinazoline ring and is —Cl, —CH₃, —CH₂CH₃, —F, —CF₃, —OCF₃, —CONHCH₃,—CONHCH₂CH₃, —CONH(cyclopropyl), —OCH₃, —NH₂, —OCH₂CH₃, or —CN.

In yet other embodiments, x is 1 and R³ is at the 7-position of thequinazoline ring and is —Cl, —CH₃, —CH₂CH₃, —F, —CF₃, —OCF₃, —CONHCH₃,—CONHCH₂CH₃, —CONH(cyclopropyl), —OCH₃, —NH₂, —OCH₂CH₃, or —CN.

In still other embodiments, x is 1 and R³ is at the 6-position of thequinazoline ring and is —Cl, —CH₃, —CH₂CH₃, —F, —CF₃, —OCF₃, —OCH₃, or—OCH₂CH₃.

In yet other embodiments, x is 1 and R³ is at the 7-position of thequinazoline ring and is —Cl, —CH₃, —CH₂CH₃, —F, —CF₃, —OCF₃, —OCH₃, or—OCH₂CH₃.

In still other embodiments, x is 1 and R³ is at the 6-position of thequinazoline ring and is —CON(R′)₂, or NRCOR′.

In yet other embodiments, x is 1 and R³ is at the 7-position of thequinazoline ring and is —Cl, —CH₃, —CH₂CH₃, —F, —CF₃, —OCF₃, —OCH₃, or—OCH₂CH₃.

In yet other embodiments for compounds described directly above, x is 1and R³ is at the 6-position of the quinazoline ring and is —Cl, —CH₃,—CH₂CH₃, —F, —CF₃, —OCF₃, —CONHCH₃, —CONHCH₂CH₃, —CONH(cyclopropyl),—OCH₃, —NH₂, —OCH₂CH₃, or —CN. In still other embodiments, x is 1 and R³is at the 7-position of the quinazoline ring and is —Cl, —CH₃, —CH₂CH₃,—F, —CF₃, —OCF₃, —CONHCH₃, —CONHCH₂CH₃, —CONH(cyclopropyl), —OCH₃, —NH₂,—OCH₂CH₃, or —CN. In yet other embodiments, x is 1 and R³ is at the6-position of the quinazoline ring and is —Cl, —CH₃, —CH₂CH₃, —F, —CF₃,—OCF₃, —OCH₃, or —OCH₂CH₃. In still other embodiments, x is 1 and R³ isat the 7-position of the quinazoline ring and is —Cl, —CH₃, —CH₂CH₃, —F,—CF₃, —OCF₃, —OCH₃, or —OCH₂CH₃. In yet other embodiments, x is 1 and R³is at the 6-position of the quinazoline ring and is —CON(R′)₂, orNRCOR′. In yet other embodiments, x is 1 and R³ is at the 7-position ofthe quinazoline ring and is —CON(R′)₂, or NRCOR′.

In one embodiment, the present invention provides compounds of formulaI-A:

wherein x, y, n₁, m₁, z₁, R^(XY), R⁴, R⁵, Sp¹, and ring B¹ are asdefined above.

In one embodiment, Sp¹ is selected from —O—, —S—, or —NR′—. Or, Sp¹ is—O—. Or, Sp¹ is —O—CH₂—. In another embodiment, Sp¹ is —NR′—. Or, Sp¹ is—NH—. Or, Sp¹ is —NH—CH₂—.

In one embodiment, each of m₁ and n₁ is 1. In another embodiment, eachof m₁ and n₁ is 2.

In one embodiment, ring B¹ is a 4-8 membered, saturated, partiallyunsaturated, or aromatic, monocyclic heterocyclic ring having 1-4heteroatoms selected from O, S, or N, wherein ring B¹ is optionallysubstituted with w independent occurrences of —R¹¹, wherein w₁ is 0-4.

In another embodiment, ring B¹ is a 4-8 membered, saturated, monocyclicheterocyclic ring having 1-4 heteroatoms selected from O, S, or N,wherein ring B¹ is optionally substituted with w independent occurrencesof —R¹¹, wherein w₁ is 0-4.

In yet another embodiment, ring B¹ is a 5-6 membered, saturated,monocyclic heterocyclic ring having 1-2 heteroatoms selected from O, S,or N, wherein ring B¹ is optionally substituted with w independentoccurrences of —R¹¹, wherein w₁ is 0-4.

In one embodiment, w₁ is 0.

In another embodiment, ring B¹ is tetrahydrofuranyl.

In yet another embodiment, Sp¹ is a bond, 0, or —O—CH₂—; R is hydrogen;and n₁ and m₁ are both simultaneously 1 or 2.

In one embodiment, R is hydrogen. Or, R is C₁-C₆ alkyl. Preferred Rinclude methyl, ethyl, propyl, or butyl.

In another embodiment, z₁ is 0.

According to another embodiment, ring B¹ is tetrahydrofuranyl,tetrahydro-[2H]-pyranyl, pyridyl, or phenyl.

According to yet another embodiment, Sp¹ is a bond, —O—, —O—CH₂—, or—NH—CH₂.

In one embodiment:

-   -   n₁ and m₁ each is 2;    -   R^(xy) is hydrogen;    -   y is 0 or 1 and R⁵ is fluoro;    -   x is 1 and R³ is Me at 7-position or fluoro at 6-position;    -   z₁ is 0;    -   Sp¹ is —O—CH₂—;    -   w₁ is 0; and    -   ring B¹ is tetrahydrofuran-3-yl, phenyl, pyridine-3-yl,        pyridine-4-yl, or tetrahydro[2H]-pyran-4-yl.

According to another embodiment, the present invention providescompounds of formula I-B:

wherein x, y, n₂, m₂, z₂, q₂, R, Sp², ring B², R^(XY), R³, R⁴, and R⁵are as defined above.

In one embodiment, G₂ is N. Or, G₂ is CH.

In one embodiment, p₂ is 0. Or, p₂ is 1. Or, p₂ is 2.

In another embodiment, q₂ is 0. Or, q₂ is 1.

In one embodiment, p₂ is 1, and q₂ is 1.

In another embodiment, G₂ is CH, p₂ is 0, and q₂ is 1.

In one embodiment, m₂ and n₂ each is 1. Or, m₂ and n₂ each is 2. Or, n₂is 1 and m₂ is 2. Or, n₂ is 1, and m₂ is 3.

In another embodiment, Sp² is selected from —O—, —S—, or —NR′—. In oneembodiment, Sp² is —O—. Or, Sp² is —NR′—. Or, Sp² is —NH—.

In one embodiment, ring B² is a 4-8 membered, saturated, partiallyunsaturated, or aromatic, monocyclic heterocyclic ring having 1-4heteroatoms selected from O, S, or N, wherein ring B is optionallysubstituted with w independent occurrences of —R¹², wherein w₂ is 0-4.

In another embodiment, ring B² is a 4-8 membered, saturated, monocyclicheterocyclic ring having 1-4 heteroatoms selected from O, S, or N,wherein ring B is optionally substituted with w independent occurrencesof —R¹², wherein w₂ is 0-4.

In yet another embodiment, ring B² is a 5-6 membered, saturated,monocyclic heterocyclic ring having 1-2 heteroatoms selected from O, S,or N, wherein ring B² is optionally substituted with w independentoccurrences of —R¹², wherein w₂ is 0-4.

In one embodiment, w₂ is 0.

According to yet another embodiment, Sp² is a bond, —O—, or —O—CH₂—.

In another embodiment, ring B² is tetrahydrofuranyl,tetrahydro[2H]pyranyl, or pyridyl.

In yet another embodiment,

-   -   i) Sp² is a bond, 0, or —O—CH₂—;    -   ii) p₂ is 1;    -   iii) R is hydrogen; and    -   iv) n₂ is 1 and m₂ is 2 or 3.

In one embodiment, R is hydrogen. Or, R is C1-C6 alkyl. Preferred Rinclude methyl, ethyl, propyl, or butyl.

In one embodiment, compounds of formula I-B have formula I-B-i orformula I-B-ii:

In one embodiment of formula I-B-i:

-   -   i) p₂ is 1;    -   ii) m₂ is 3;    -   iii) Sp² is —O—;    -   iv) y is 0 or 1, and R⁵ is fluoro;    -   v) x is 1 and R³ is 7-Me; and    -   vi) ring B is tetrahydrofuranyl.

In another embodiment of formula I-B-i:

-   -   i) p₂ is 0 or 1;    -   ii) m₂ is 1 or 2, preferably 2;    -   iii) Sp² is —O— or —O—CH₂—;    -   iv) y is 0;    -   v) x is 1 and R³ is 7-Me; and    -   vi) ring B² is tetrahydrofuranyl, tetrahydro[2H]pyranyl,        pyridyl, or phenyl.

In one embodiment of formula I-B-ii:

-   -   (i) n₂ is 1, m₂ is 1 or 2, preferably 2;    -   (ii) y is 0 or 1, and R⁵ is fluoro;    -   (iii) x is 1 and R³ is 7-Me or 6-F; and    -   (iv) ring B² is cyclopropyl optionally substituted with C1-C4        alkyl, or pyridyl.

In one embodiment of formula I-B-ii:

-   -   (i) n₂ and m₂ both are 2;    -   (ii) y is 0;    -   (iii) x is 1 and R³ is C1-C4 alkyl at the 7-position; and    -   (iv) ring B² is an optionally substituted tetrahydrofuranyl.

In one embodiment of formula I-B-i or formula I-B-ii, R^(XY) ishydrogen.

According to one embodiment, the present invention provides compounds offormula I-C or formula I-D:

wherein x, y, n₃, m₃, z₃, p₃, R^(XX), R^(YY), R^(XY), R³, R⁴, and R⁵ areas defined above.

In one embodiment of the present invention, one R^(XX) is hydrogen andthe other R^(XX) is not hydrogen.

In another embodiment of the present invention, both R^(XX) are nothydrogen.

In another embodiment, one R^(XX) is hydrogen and the other R^(XX) isC1-C6 alkyl optionally substituted with halo. Or, both R^(XX) aresimultaneously C1-C6 alkyl. Exemplary alkyl include methyl, ethyl,isopropyl, n-propyl, n-butyl, sec-butyl, or t-butyl.

In one embodiment of the present invention, p₃ is 0. Or, p₃ is 1. Or, p₃is 2.

In one embodiment of the present invention, m₃ and n₃ each is 1. Or, m₃and n₃ each is 2. Or, m₃ and n₃ each is 3.

In one embodiment of the present invention, R^(XX) is C₁₋₆ aliphaticgroup, wherein R^(XX) is optionally substituted with w independentoccurrences of —R¹³, wherein w₃ is 0-3. Or, R^(XX) is C1-C6 alkyl groupoptionally substituted with w₃ independent occurrences of —R¹³, whereinw₃ is 0-3.

In one embodiment of the present invention, R^(XX) is C1-C6 alkyl group.

In another embodiment of the present invention, R^(XX) is a 3-8-memberedsaturated, partially unsaturated, or fully unsaturated monocyclic ringhaving 0-3 heteroatoms independently selected from nitrogen, oxygen, orsulfur, or an 8-12 membered saturated, partially unsaturated, or fullyunsaturated bicyclic ring system having 0-5 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur, wherein R^(XX) is optionallysubstituted with w₃ independent occurrences of —R¹³, wherein w₃ is 0-3.

In another embodiment, R^(XX) is a 3-8-membered saturated, partiallyunsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, wherein R^(XX)is optionally substituted with w independent occurrences of —R¹³,wherein w₃ is 0-3.

In another embodiment, R^(XX) is an 8-12 membered saturated, partiallyunsaturated, or fully unsaturated bicyclic ring system having 0-5heteroatoms independently selected from nitrogen, oxygen, or sulfur,wherein R^(XX) is optionally substituted with W₃ independent occurrencesof —R¹³, wherein w₃ is 0-3.

In another embodiment, R^(YY) is hydrogen, —COR′, —CO₂R′, —CON(R′)₂,—SOR′, —SO₂R′, —SO₂N(R′)₂, —COCOR′, —COCH₂COR′, —P(O)(OR′)₂, —P(O)₂OR′,or —PO(R′).

Or, R^(YY) is hydrogen.

In another embodiment, R^(YY) is —COR′, —CO₂R′, —CON(R′)₂, —SOR′,—SO₂R′, —SO₂N(R′)₂, —COCOR′, —COCH₂COR′, —P(O)(OR′)₂, —P(O)₂OR′, or—PO(R′).

In another embodiment, R^(YY) is R^(XY).

In one embodiment, R is hydrogen. Or, R is C1-C6 alkyl. Preferred Rinclude methyl, ethyl, propyl, or butyl.

In one embodiment, the present invention provides a compound of formulaI-C-i or formula I-D-i:

wherein x, y, n₃, m₃, z₃, p₃, R^(XX), R^(YY), R^(XY), R³, R⁴, and R⁵ areas defined above.

In one embodiment of 1-C-i or I-D-i, R^(XX) is C1-C6 alkyl. In anotherembodiment, x is 1, and R³ is C1-C4 alkyl at the 7-position. Or, x is 1and R³ is F, CN, or CF₃ at the 6-position.

In one embodiment, R^(XX) is methyl, n-propyl, isopropyl, n-butyl,sec-butyl, or t-butyl.

In one embodiment, R³ is C1-C6 alkyl. Or, R³ is methyl, n-propyl,isopropyl, n-butyl, sec-butyl, or t-butyl.

In one embodiment of 1-C-i or I-D-i, R^(XY) is hydrogen, and y is 0. Or,R^(XY) is hydrogen, y is 1 and R⁵ is 6-F.

In another embodiment, the present invention provides a compound offormula I-C-ii:

wherein R³ and R^(XX) are as defined above.

In another embodiment, R³ is methyl at the 6- or 7-position of thequinazoline ring.

In another embodiment of formula I-C-ii, R^(XX) is CH₂C(O)OH orCH₂C(O)NH₂.

According to one embodiment, the present invention provides a compoundof formula I-E:

wherein x, y, n₄, m₄, z₄, p₄, R^(YZ), R^(XY), R³, R⁴, and R⁵ are asdefined above.

In one embodiment, p₄ is 1. Or, p₄ is 2.

In one embodiment, m₄ and n₄ each is 1. Or, m₄ and n₄ each is 2. Or, m₄and n₄ each is 3. In one embodiment, n₄ is 1 and m₄ is 3. In anotherembodiment, n₄ is 1 and m₄ is 2.

In one embodiment, n₄ is 1, m₄ is 3, Z₄ is 0, p₄ is 1, y is 0 or 1, andx is 1.

In another embodiment, n₄ is l, m₄ is 2, z₄ is 0, p₄ is 1, y is 0 or 1,and x is 1.

In one embodiment, n₄ is l, m₄ is 3, Z₄ is 0, p₄ is 1, y is 0 or 1, x is1, and R and R^(XY) both are hydrogen.

In another embodiment, n₄ is 1, m₄ is 2, Z₄ is 0, p₄ is 1, y is 0 or 1,x is 1, and R and R^(XY) both are hydrogen.

In one embodiment, R^(YZ) is C1-C6 alkyl, optionally substituted with W₄independent occurrences of —R¹⁴, wherein w₄ is 0-3. In anotherembodiment, R^(YZ) is C1-C4 alkyl group optionally substituted with w₄independent occurrences of —R¹⁴, wherein W₄ is 0-3. Or, R^(Y) is C1-C6alkyl group.

In one embodiment, R is hydrogen. Or, R is C1-C6 alkyl. Preferred Rinclude methyl, ethyl, propyl, or butyl.

In another embodiment:

-   -   (i) n₄ is 1 and m₄ is 3;    -   (ii) p₄ is 1;    -   (iii) z₄ is 0;    -   (iv) R^(YZ) is C1-C6 alkyl, wherein up to two —CH₂— groups        therein is optionally replaced by —O—;    -   (v) y is 0 or 1, and R⁵ is 6-fluoro; and    -   (vi) x is 1 and R³ is C1-C4 alkyl.

In another embodiment:

-   -   (i) n₄ is 1 and m₄ is 2;    -   (ii) p₄ is 1;    -   (iii) Z₄ is 0;    -   (iv) R^(YZ) is C1-C6 alkyl, wherein up to two —CH₂— groups        therein is optionally replaced by —O—;    -   (v) y is 0 or 1, and R⁵ is 6-fluoro; and    -   (vi) x is 1 and R³ is C1-C4 alkyl.

In another embodiment:

-   -   (i) n₄ is 1 and m₄ is 3;    -   (ii) p₄ is 1;    -   (iii) Z₄ is 0;    -   (iv) R^(YZ) is benzyl;    -   (v) y is 0 or 1, and R⁵ is 6-fluoro; and    -   (vi) x is 1 and R³ is C1-C4 alkyl.

In one embodiment, the present invention provides compounds shown belowin Table 2.

TABLE 2 101

102

103

104

105

106

107

108

109

110

111

112

113

114

115

116

117

118

119

120

121

122

123

124

125

126

127

128

129

130

131

132

133

134

135

136

137

138

139

140

141

142

143

144

145

146

147

148

149

150

151

152

153

154

155

156

157

158

159

160

162

163

164

165

166

167

168

169

170

171

172

173

174

175

176

177

178

179

180

181

182

183

184

185

201

203

204

205

206

207

208

209

210

211

212

213

214

215

216

217

218

219

220

221

222

223

224

225

226

227

228

229

230

231

232

233

234

235

236

237

238

239

240

241

242

243

244

245

246

247

248

249

250

251

252

253

254

255

256

257

258

259

260

261

262

264

265

266

267

268

269

270

271

272

273

274

275

276

277

278

279

301

302

303

304

305

306

307

308

309

310

311

312

313

314

315

316

317

318

319

320

321

322

323

324

325

326

327

328

329

330

331

332

333

334

335

336

337

338

339

340

341

342

343

344

345

346

347

348

349

350

351

352

353

354

355

356

357

358

359

360

361

362

363

364

365

366

367

368

369

370

371

372

373

374

375

376

377

401

402

415

416

417

418

419

420

186

187

188

189

190

191

192

193

194

195

196

197

280

281

282

283

378

379

380

4. General Synthetic Methodology

The compounds of this invention may be prepared in general by methodsknown to those skilled in the art for analogous compounds, asillustrated by the general schemes below, and the preparative examplesthat follow.

5. Uses, Formulation and Administration

WO 2004/078733 discloses a genus of sodium channel blockers thatencompasses the compounds of the present invention. However, thecompounds of the present invention exhibit unexpected properties setforth below that render them therapeutically more useful.

In one embodiment, certain compounds of the present invention are usefulas improved inhibitors of sodium channels.

In another embodiment, certain compounds of the present inventionpossess improved selectivity in inhibiting one sodium channel, e.g., NaV1.8, over one or more of the other sodium channels. Particularly usefulare compounds that have a desirably low activity against NaV 1.2 or NaV1.5.

In another embodiment, certain compounds of the present invention areimproved inhibitors of NaV 1.8.

In another embodiment, certain compounds of the present invention haveimproved aqueous solubility, e.g., at physiologically relevant pH.

In yet another embodiment, certain compounds of the present inventionhave improved pharmacokinetic and/or pharmacodynamic properties and,therefore, are better suited for in-vivo administration for therapeuticpurposes. Such properties include oral bioavailability, clearancekinetics, efficacy, etc.

In another embodiment, certain compounds of the present invention havedesirably low activity against the hERG channel.

In another embodiment, certain compounds of the present invention havedesirably low activity against the key isoforms of the cytochrome P450enzyme family, including isozymes CYP3A4, CYP2C9, CYP1A2, CYP2C19, orCYP2D6.

In another embodiment, certain compounds of the present invention havedesirably low activity against the CaV 1.2 channel and/or Kv 1.5.

Thus, in one embodiment of the present invention, the compounds have oneor more of the following unexpected and therapeutically beneficialfeatures: potent inhibition of NaV 1.8 channel, selectivity for onesodium channel, e.g., NaV 1.8 over one or more of the other sodiumchannels, improved aqueous solubility, improved pharmacokinetic and/orpharmacodynamic properties, desirably low activity against the hERGchannel, desirably low activity against the key isoforms of thecytochrome P450 enzyme family, or desirably low activity against L-typeCaV 1.2 and/or Kv1.5. The presence of such features, individually or incombination, renders the compounds more suitable for administration tohumans to treat various diseases as set forth below.

The phrase “desirably low activity” as used herein means a level ofactivity of a compound against a target/enzyme that is low enough suchthat said activity would be considered advantageous (e.g., mitigating arisk factor), when evaluating the suitability of said compound foradministration in humans.

The present compounds are useful for the treatment of diseases,disorders, and conditions including, but not limited to acute, chronic,neuropathic, or inflammatory pain, arthritis, migraine, clusterheadaches, trigeminal neuralgia, herpetic neuralgia, general neuralgias,epilepsy or epilepsy conditions, neurodegenerative disorders,psychiatric disorders such as anxiety and depression, myotonia,arrhythmia, movement disorders, neuroendocrine disorders, ataxia,multiple sclerosis, irritable bowel syndrome, and incontinence.Accordingly, in another aspect of the present invention,pharmaceutically acceptable compositions are provided, wherein thesecompositions comprise any of the compounds as described herein, andoptionally comprise a pharmaceutically acceptable carrier, adjuvant orvehicle. In certain embodiments, these compositions optionally furthercomprise one or more additional therapeutic agents.

According to one embodiment, the compounds of the present invention areuseful for treating a disease selected from femur cancer pain;non-malignant chronic bone pain; rheumatoid arthritis; osteoarthritis;spinal stenosis; neuropathic low back pain; neuropathic low back pain;myofascial pain syndrome; fibromyalgia; temporomandibular joint pain;chronic visceral pain, including, abdominal; pancreatic; IBS pain;chronic headache pain; migraine; tension headache, including, clusterheadaches; chronic neuropathic pain, including, post-herpetic neuralgia;diabetic neuropathy; HIV-associated neuropathy; trigeminal neuralgia;Charcot-Marie Tooth neuropathy; hereditary sensory neuropathies;peripheral nerve injury; painful neuromas; ectopic proximal and distaldischarges; radiculopathy; chemotherapy induced neuropathic pain;radiotherapy-induced neuropathic pain; post-mastectomy pain; centralpain; spinal cord injury pain; post-stroke pain; thalamic pain; complexregional pain syndrome; phantom pain; intractable pain; acute pain,acute post-operative pain; acute musculoskeletal pain; joint pain;mechanical low back pain; neck pain; tendonitis; injury/exercise pain;acute visceral pain, including, abdominal pain; pyelonephritis;appendicitis; cholecystitis; intestinal obstruction; hernias; etc; chestpain, including, cardiac Pain; pelvic pain, renal colic pain, acuteobstetric pain, including, labor pain; cesarean section pain; acuteinflammatory, burn and trauma pain; acute intermittent pain, including,endometriosis; acute herpes zoster pain; sickle cell anemia; acutepancreatitis; breakthrough pain; orofacial pain, including, sinusitispain, dental pain; multiple sclerosis (MS) pain; pain in depression;leprosy pain; Behcet's disease pain; adiposis dolorosa; phlebitic pain;Guillain-Barre pain; painful legs and moving toes; Haglund syndrome;erythromelalgia pain; Fabry's disease pain; bladder and urogenitaldisease, including, urinary incontinence; hyperactivity bladder; painfulbladder syndrome; interstitial cystitis (IC); and prostatitis.

In another embodiment, the compounds of the present invention are usefulin treating lower urinary tract disorders. See, e.g., InternationalPatent Publication No. WO 2004/066990, the contents of which areincorporated herein by reference.

It will also be appreciated that certain of the compounds of presentinvention can exist in free form for treatment, or where appropriate, asa pharmaceutically acceptable derivative thereof. According to thepresent invention, a pharmaceutically acceptable derivative includes,but is not limited to, pharmaceutically acceptable salts, esters, saltsof such esters, or any other adduct or derivative which uponadministration to a patient in need is capable of providing, directly orindirectly, a compound as otherwise described herein, or a metabolite orresidue thereof.

As used herein, the term “pharmaceutically acceptable salt” refers tothose salts which are, within the scope of sound medical judgment,suitable for use in contact with the tissues of humans and lower animalswithout undue toxicity, irritation, allergic response and the like, andare commensurate with a reasonable benefit/risk ratio. A“pharmaceutically acceptable salt” means any non-toxic salt or salt ofan ester of a compound of this invention that, upon administration to arecipient, is capable of providing, either directly or indirectly, acompound of this invention or an inhibitory active metabolite or residuethereof. As used herein, the term “inhibitorily active metabolite orresidue thereof” means that a metabolite or residue thereof is also aninhibitor of the targeted channel.

Pharmaceutically acceptable salts are well known in the art. Forexample, S. M. Berge, et al. describe pharmaceutically acceptable saltsin detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporatedherein by reference. Pharmaceutically acceptable salts of the compoundsof this invention include those derived from suitable inorganic andorganic acids and bases. Examples of pharmaceutically acceptable,nontoxic acid addition salts are salts of an amino group formed withinorganic acids such as hydrochloric acid, hydrobromic acid, phosphoricacid, sulfuric acid and perchloric acid or with organic acids such asacetic acid, oxalic acid, maleic acid, tartaric acid, citric acid,succinic acid or malonic acid or by using other methods used in the artsuch as ion exchange. Other pharmaceutically acceptable salts includeadipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate,bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate,cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate,formate, fumarate, glucoheptonate, glycerophosphate, gluconate,hemisulfate, heptanoate, hexanoate, hydroiodide,2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, laurylsulfate, malate, maleate, malonate, methanesulfonate,2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate,pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate,pivalate, propionate, stearate, succinate, sulfate, tartrate,thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and thelike. Salts derived from appropriate bases include alkali metal,alkaline earth metal, ammonium and N⁺(C₁₋₄alkyl)₄ salts. This inventionalso envisions the quaternization of any basic nitrogen-containinggroups of the compounds disclosed herein. Water or oil-soluble ordispersable products may be obtained by such quaternization.Representative alkali or alkaline earth metal salts include sodium,lithium, potassium, calcium, magnesium, and the like. Furtherpharmaceutically acceptable salts include, when appropriate, nontoxicammonium, quaternary ammonium, and amine cations formed usingcounterions such as halide, hydroxide, carboxylate, sulfate, phosphate,nitrate, loweralkyl sulfonate and aryl sulfonate.

As described above, the pharmaceutically acceptable compositions of thepresent invention additionally comprise a pharmaceutically acceptablecarrier, adjuvant, or vehicle, which, as used herein, includes any andall solvents, diluents, or other liquid vehicle, dispersion orsuspension aids, surface active agents, isotonic agents, thickening oremulsifying agents, preservatives, solid binders, lubricants and thelike, as suited to the particular dosage form desired. Remington'sPharmaceutical Sciences, Sixteenth Edition, E. W. Martin (MackPublishing Co., Easton, Pa., 1980) discloses various carriers used informulating pharmaceutically acceptable compositions and knowntechniques for the preparation thereof. Except insofar as anyconventional carrier medium is incompatible with the compounds of theinvention, such as by producing any undesirable biological effect orotherwise interacting in a deleterious manner with any othercomponent(s) of the pharmaceutically acceptable composition, its use iscontemplated to be within the scope of this invention. Some examples ofmaterials which can serve as pharmaceutically acceptable carriersinclude, but are not limited to, ion exchangers, alumina, aluminumstearate, lecithin, serum proteins, such as human serum albumin, buffersubstances such as phosphates, glycine, sorbic acid, or potassiumsorbate, partial glyceride mixtures of saturated vegetable fatty acids,water, salts or electrolytes, such as protamine sulfate, disodiumhydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zincsalts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone,polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, woolfat, sugars such as lactose, glucose and sucrose; starches such as cornstarch and potato starch; cellulose and its derivatives such as sodiumcarboxymethyl cellulose, ethyl cellulose and cellulose acetate; powderedtragacanth; malt; gelatin; talc; excipients such as cocoa butter andsuppository waxes; oils such as peanut oil, cottonseed oil; saffloweroil; sesame oil; olive oil; corn oil and soybean oil; glycols; such apropylene glycol or polyethylene glycol; esters such as ethyl oleate andethyl laurate; agar; buffering agents such as magnesium hydroxide andaluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline;Ringer's solution; ethyl alcohol, and phosphate buffer solutions, aswell as other non-toxic compatible lubricants such as sodium laurylsulfate and magnesium stearate, as well as coloring agents, releasingagents, coating agents, sweetening, flavoring and perfuming agents,preservatives and antioxidants can also be present in the composition,according to the judgment of the formulator.

Uses of Compounds and Pharmaceutically Acceptable Compositions

In yet another aspect, a method for the treatment or lessening theseverity of acute, chronic, neuropathic, or inflammatory pain,arthritis, migraine, cluster headaches, trigeminal neuralgia, herpeticneuralgia, general neuralgias, epilepsy or epilepsy conditions,neurodegenerative disorders, psychiatric disorders such as anxiety anddepression, myotonia, arrhythmia, movement disorders, neuroendocrinedisorders, ataxia, multiple sclerosis, irritable bowel syndrome,incontinence, visceral pain, osteoarthritis pain, postherpeticneuralgia, diabetic neuropathy, radicular pain, sciatica, back pain,head or neck pain, severe or intractable pain, nociceptive pain,breakthrough pain, postsurgical pain, or cancer pain is providedcomprising administering an effective amount of a compound, or apharmaceutically acceptable composition comprising a compound to asubject in need thereof. In certain embodiments, a method for thetreatment or lessening the severity of acute, chronic, neuropathic, orinflammatory pain is provided comprising administering an effectiveamount of a compound or a pharmaceutically acceptable composition to asubject in need thereof. In certain other embodiments, a method for thetreatment or lessening the severity of radicular pain, sciatica, backpain, head pain, or neck pain is provided comprising administering aneffective amount of a compound or a pharmaceutically acceptablecomposition to a subject in need thereof. In still other embodiments, amethod for the treatment or lessening the severity of severe orintractable pain, acute pain, postsurgical pain, back pain, or cancerpain is provided comprising administering an effective amount of acompound or a pharmaceutically acceptable composition to a subject inneed thereof.

In certain embodiments of the present invention an “effective amount” ofthe compound or pharmaceutically acceptable composition is that amounteffective for treating or lessening the severity of one or more ofacute, chronic, neuropathic, or inflammatory pain, arthritis, migraine,cluster headaches, trigeminal neuralgia, herpetic neuralgia, generalneuralgias, epilepsy or epilepsy conditions, neurodegenerativedisorders, psychiatric disorders such as anxiety and depression,myotonia, arrhythmia, movement disorders, neuroendocrine disorders,ataxia, multiple sclerosis, irritable bowel syndrome, incontinence,visceral pain, osteoarthritis pain, postherpetic neuralgia, diabeticneuropathy, radicular pain, sciatica, back pain, head or neck pain,severe or intractable pain, nociceptive pain, breakthrough pain,postsurgical pain, or cancer pain.

The compounds and compositions, according to the method of the presentinvention, may be administered using any amount and any route ofadministration effective for treating or lessening the severity of oneor more of acute, chronic, neuropathic, or inflammatory pain, arthritis,migraine, cluster headaches, trigeminal neuralgia, herpetic neuralgia,general neuralgias, epilepsy or epilepsy conditions, neurodegenerativedisorders, psychiatric disorders such as anxiety and depression,myotonia, arrhythmia, movement disorders, neuroendocrine disorders,ataxia, multiple sclerosis, irritable bowel syndrome, incontinence,visceral pain, osteoarthritis pain, postherpetic neuralgia, diabeticneuropathy, radicular pain, sciatica, back pain, head or neck pain,severe or intractable pain, nociceptive pain, breakthrough pain,postsurgical pain, or cancer pain. The exact amount required will varyfrom subject to subject, depending on the species, age, and generalcondition of the subject, the severity of the infection, the particularagent, its mode of administration, and the like. The compounds of theinvention are preferably formulated in dosage unit form for ease ofadministration and uniformity of dosage. The expression “dosage unitform” as used herein refers to a physically discrete unit of agentappropriate for the patient to be treated. It will be understood,however, that the total daily usage of the compounds and compositions ofthe present invention will be decided by the attending physician withinthe scope of sound medical judgment. The specific effective dose levelfor any particular patient or organism will depend upon a variety offactors including the disorder being treated and the severity of thedisorder; the activity of the specific compound employed; the specificcomposition employed; the age, body weight, general health, sex and dietof the patient; the time of administration, route of administration, andrate of excretion of the specific compound employed; the duration of thetreatment; drugs used in combination or coincidental with the specificcompound employed, and like factors well known in the medical arts. Theterm “patient”, as used herein, means an animal, preferably a mammal,and most preferably a human.

The pharmaceutically acceptable compositions of this invention can beadministered to humans and other animals orally, rectally, parenterally,intracisternally, intravaginally, intraperitoneally, topically (as bypowders, ointments, or drops), bucally, as an oral or nasal spray, orthe like, depending on the severity of the infection being treated. Incertain embodiments, the compounds of the invention may be administeredorally or parenterally at dosage levels of about 0.01 mg/kg to about 50mg/kg and preferably from about 1 mg/kg to about 25 mg/kg, of subjectbody weight per day, one or more times a day, to obtain the desiredtherapeutic effect.

Liquid dosage forms for oral administration include, but are not limitedto, pharmaceutically acceptable emulsions, microemulsions, solutions,suspensions, syrups and elixirs. In addition to the active compounds,the liquid dosage forms may contain inert diluents commonly used in theart such as, for example, water or other solvents, solubilizing agentsand emulsifiers such as ethyl alcohol, isopropyl alcohol, ethylcarbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1,3-butylene glycol, dimethylformamide, oils (in particular,cottonseed, groundnut, corn, germ, olive, castor, and sesame oils),glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fattyacid esters of sorbitan, and mixtures thereof. Besides inert diluents,the oral compositions can also include adjuvants such as wetting agents,emulsifying and suspending agents, sweetening, flavoring, and perfumingagents.

Injectable preparations, for example, sterile injectable aqueous oroleaginous suspensions may be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation may also be a sterile injectablesolution, suspension or emulsion in a nontoxic parenterally acceptablediluent or solvent, for example, as a solution in 1,3-butanediol. Amongthe acceptable vehicles and solvents that may be employed are water,Ringer's solution, U.S.P. and isotonic sodium chloride solution. Inaddition, sterile, fixed oils are conventionally employed as a solventor suspending medium. For this purpose any bland fixed oil can beemployed including synthetic mono- or diglycerides. In addition, fattyacids such as oleic acid are used in the preparation of injectables.

The injectable formulations can be sterilized, for example, byfiltration through a bacterial-retaining filter, or by incorporatingsterilizing agents in the form of sterile solid compositions which canbe dissolved or dispersed in sterile water or other sterile injectablemedium prior to use.

In order to prolong the effect of a compound of the present invention,it is often desirable to slow the absorption of the compound fromsubcutaneous or intramuscular injection. This may be accomplished by theuse of a liquid suspension of crystalline or amorphous material withpoor water solubility. The rate of absorption of the compound thendepends upon its rate of dissolution that, in turn, may depend uponcrystal size and crystalline form. Alternatively, delayed absorption ofa parenterally administered compound form is accomplished by dissolvingor suspending the compound in an oil vehicle. Injectable depot forms aremade by forming microencapsulated matrices of the compound inbiodegradable polymers such as polylactide-polyglycolide. Depending uponthe ratio of compound to polymer and the nature of the particularpolymer employed, the rate of compound release can be controlled.Examples of other biodegradable polymers include poly(orthoesters) andpoly(anhydrides). Depot injectable formulations are also prepared byentrapping the compound in liposomes or microemulsions that arecompatible with body tissues.

Compositions for rectal or vaginal administration are preferablysuppositories which can be prepared by mixing the compounds of thisinvention with suitable non-irritating excipients or carriers such ascocoa butter, polyethylene glycol or a suppository wax which are solidat ambient temperature but liquid at body temperature and therefore meltin the rectum or vaginal cavity and release the active compound.

Solid dosage forms for oral administration include capsules, tablets,pills, powders, and granules. In such solid dosage forms, the activecompound is mixed with at least one inert, pharmaceutically acceptableexcipient or carrier such as sodium citrate or dicalcium phosphateand/or a) fillers or extenders such as starches, lactose, sucrose,glucose, mannitol, and silicic acid, b) binders such as, for example,carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone,sucrose, and acacia, c) humectants such as glycerol, d) disintegratingagents such as agar-agar, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates, and sodium carbonate, e) solutionretarding agents such as paraffin, f) absorption accelerators such asquaternary ammonium compounds, g) wetting agents such as, for example,cetyl alcohol and glycerol monostearate, h) absorbents such as kaolinand bentonite clay, and i) lubricants such as talc, calcium stearate,magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate,and mixtures thereof. In the case of capsules, tablets and pills, thedosage form may also comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers insoft and hard-filled gelatin capsules using such excipients as lactoseor milk sugar as well as high molecular weight polyethylene glycols andthe like. The solid dosage forms of tablets, dragees, capsules, pills,and granules can be prepared with coatings and shells such as entericcoatings and other coatings well known in the pharmaceutical formulatingart. They may optionally contain opacifying agents and can also be of acomposition that they release the active ingredient(s) only, orpreferentially, in a certain part of the intestinal tract, optionally,in a delayed manner. Examples of embedding compositions that can be usedinclude polymeric substances and waxes. Solid compositions of a similartype may also be employed as fillers in soft and hard-filled gelatincapsules using such excipients as lactose or milk sugar as well as highmolecular weight polyethylene glycols and the like.

The active compounds can also be in microencapsulated form with one ormore excipients as noted above. The solid dosage forms of tablets,dragees, capsules, pills, and granules can be prepared with coatings andshells such as enteric coatings, release controlling coatings and othercoatings well known in the pharmaceutical formulating art. In such soliddosage forms the active compound may be admixed with at least one inertdiluent such as sucrose, lactose or starch. Such dosage forms may alsocomprise, as is normal practice, additional substances other than inertdiluents, e.g., tableting lubricants and other tableting aids such amagnesium stearate and microcrystalline cellulose. In the case ofcapsules, tablets and pills, the dosage forms may also comprisebuffering agents. They may optionally contain opacifying agents and canalso be of a composition that they release the active ingredient(s)only, or preferentially, in a certain part of the intestinal tract,optionally, in a delayed manner. Examples of embedding compositions thatcan be used include polymeric substances and waxes.

Dosage forms for topical or transdermal administration of a compound ofthis invention include ointments, pastes, creams, lotions, gels,powders, solutions, sprays, inhalants or patches. The active componentis admixed under sterile conditions with a pharmaceutically acceptablecarrier and any needed preservatives or buffers as may be required.Ophthalmic formulation, eardrops, and eye drops are also contemplated asbeing within the scope of this invention. Additionally, the presentinvention contemplates the use of transdermal patches, which have theadded advantage of providing controlled delivery of a compound to thebody. Such dosage forms are prepared by dissolving or dispensing thecompound in the proper medium. Absorption enhancers can also be used toincrease the flux of the compound across the skin. The rate can becontrolled by either providing a rate controlling membrane or bydispersing the compound in a polymer matrix or gel.

It will also be appreciated that the compounds and pharmaceuticallyacceptable compositions of the present invention can be employed incombination therapies, that is, the compounds and pharmaceuticallyacceptable compositions can be administered concurrently with, prior to,or subsequent to, one or more other desired therapeutics or medicalprocedures. The particular combination of therapies (therapeutics orprocedures) to employ in a combination regimen will take into accountcompatibility of the desired therapeutics and/or procedures and thedesired therapeutic effect to be achieved. It will also be appreciatedthat the therapies employed may achieve a desired effect for the samedisorder (for example, an inventive compound may be administeredconcurrently with another agent used to treat the same disorder), orthey may achieve different effects (e.g., control of any adverseeffects). As used herein, additional therapeutic agents that arenormally administered to treat or prevent a particular disease, orcondition, are known as “appropriate for the disease, or condition,being treated”. For example, exemplary additional therapeutic agentsinclude, but are not limited to: nonopioid analgesics (indoles such asEtodolac, Indomethacin, Sulindac, Tolmetin; naphthylalkanones such asNabumetone; oxicams such as Piroxicam; para-aminophenol derivatives,such as Acetaminophen; propionic acids such as Fenoprofen, Flurbiprofen,Ibuprofen, Ketoprofen, Naproxen, Naproxen sodium, Oxaprozin; salicylatessuch as Asprin, Choline magnesium trisalicylate, Diflunisal; fenamatessuch as meclofenamic acid, Mefenamic acid; and pyrazoles such asPhenylbutazone); or opioid (narcotic) agonists (such as Codeine,Fentanyl, Hydromorphone, Levorphanol, Meperidine, Methadone, Morphine,Oxycodone, Oxymorphone, Propoxyphene, Buprenorphine, Butorphanol,Dezocine, Nalbuphine, and Pentazocine). Additionally, nondrug analgesicapproaches may be utilized in conjunction with administration of one ormore compounds of the invention. For example, anesthesiologic(intraspinal infusion, neural blockade), neurosurgical (neurolysis ofCNS pathways), neurostimulatory (transcutaneous electrical nervestimulation, dorsal column stimulation), physiatric (physical therapy,orthotic devices, diathermy), or psychologic (cognitivemethods-hypnosis, biofeedback, or behavioral methods) approaches mayalso be utilized. Additional appropriate therapeutic agents orapproaches are described generally in The Merck Manual, SeventeenthEdition, Ed. Mark H. Beers and Robert Berkow, Merck ResearchLaboratories, 1999, and the Food and Drug Administration website,www.fda.gov, the entire contents of which are hereby incorporated byreference.

The amount of additional therapeutic agent present in the compositionsof this invention will be no more than the amount that would normally beadministered in a composition comprising that therapeutic agent as theonly active agent. Preferably the amount of additional therapeutic agentin the presently disclosed compositions will range from about 50% to100% of the amount normally present in a composition comprising thatagent as the only therapeutically active agent.

The compounds of this invention or pharmaceutically acceptablecompositions thereof may also be incorporated into compositions forcoating an implantable medical device, such as prostheses, artificialvalves, vascular grafts, stents and catheters. Accordingly, the presentinvention, in another aspect, includes a composition for coating animplantable device comprising a compound of the present invention asdescribed generally above, and in classes and subclasses herein, and acarrier suitable for coating said implantable device. In still anotheraspect, the present invention includes an implantable device coated witha composition comprising a compound of the present invention asdescribed generally above, and in classes and subclasses herein, and acarrier suitable for coating said implantable device. Suitable coatingsand the general preparation of coated implantable devices are describedin U.S. Pat. Nos. 6,099,562; 5,886,026; and 5,304,121. The coatings aretypically biocompatible polymeric materials such as a hydrogel polymer,polymethyldisiloxane, polycaprolactone, polyethylene glycol, polylacticacid, ethylene vinyl acetate, and mixtures thereof. The coatings mayoptionally be further covered by a suitable topcoat of fluorosilicone,polysaccharides, polyethylene glycol, phospholipids or combinationsthereof to impart controlled release characteristics in the composition.

Another aspect of the invention relates to inhibiting NaV1.8 activity ina biological sample or a patient, which method comprises administeringto the patient, or contacting said biological sample with a compound ofthe present invention or a composition comprising said compound. Theterm “biological sample”, as used herein, includes, without limitation,cell cultures or extracts thereof; biopsied material obtained from amammal or extracts thereof; and blood, saliva, urine, feces, semen,tears, or other body fluids or extracts thereof.

Inhibition of NaV1.8 activity in a biological sample is useful for avariety of purposes that are known to one of skill in the art. Examplesof such purposes include, but are not limited to, the study of sodiumion channels in biological and pathological phenomena; and thecomparative evaluation of new sodium ion channel inhibitors.

In order that the invention described herein may be more fullyunderstood, the following examples are set forth. It should beunderstood that these examples are for illustrative purposes only andare not to be construed as limiting this invention in any manner.

EXAMPLES

General LC/MS Methods

LC/MS data were acquired using a PESciex API-150-EX LC/MS, ShimadzuLC-8A pumps, Gilson 215 autosampler, Gilson 819 injection module, 3.0mL/min flow rate, 10-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA) gradient,Phenomenex Luna 5u C18 column (50×4.60 mm), Shimadzu SPD-10A UV/Visdetector, Cedex 75 ELSD detector.

Example 101(R)-2-Hydroxy-1-(4-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperazin-1-yl)-4,4-dimethylpentan-1-one

N-(2-Cyano-5-methyl-phenyl)-2-methoxy-benzamide

To a stirred solution of 4-methyl-2-aminobenzonitrile (100 g, 0.75 mol)in 800 mL CH₂Cl₂ was added triethylamine (77.4 g, 0.76 mol) anddimethylaminopyridine (4.62 g, 0.037 mol). The solution was cooled to0-5° C., and o-anisoyl chloride (129 g, 0.75 mol) was added over 1 hwhile maintaining the reaction temperature at 0-5° C. The reaction wasthen stirred at 30-40° C. for 3 h. Water (400 mL) was added, and themixture was stirred for 15 minutes. The organic layer was separated, andthe aqueous solution was extracted with CH₂Cl₂ (600 mL). The combinedorganic layers were dried over sodium sulfate, filtered, andconcentrated in vacuo to yield a solid residue, to which 800 mL hexanewere added. The slurry was stirred and filtered to giveN-(2-cyano-5-methyl-phenyl)-2-methoxy-benzamide as a yellow powder (180g, 90%). mp 147-149° C. ¹H NMR (CDCl₃) δ 2.429 (s, 3H), 4.2 (s, 3H),6.8-7.2 (m, 3H), 7.4-7.6 (m, 2H), 8.2-8.4 (d, 1H), 8.6 (s, 1H), 10.8(bs, 1H); M/z (obs., [m+H]⁺)=268.

2-(2-Methoxyphenyl)-7-methyl-3H-quinazolin-4-one

To a mechanically stirred suspension ofN-(2-cyano-5-methylphenyl)-2-methoxybenzamide (180 g, 0.67 mol) in 1.8 Lethanol under an N₂ atmosphere was added 6 N sodium hydroxide solution(310 g in 1.25 L water). To the above mixture, 30% hydrogen peroxide(350 mL, 3.64 mol) was slowly added. The solution was then slowly heatedto 80° C. and maintained at this temperature for 4 h. The reactionmixture was concentrated under reduced pressure to remove ethanol,giving a suspension, which was quenched with ice-cold water (1.8 L) andacidified with acetic acid to pH 5-6 to give a solid residue. The solidwas filtered and washed with water, then dissolved in 5.5 L CH₂Cl₂ andwashed with water (2×18 L). The organic layer was dried over sodiumsulfate, and the solvent was removed under reduced pressure to give alight yellow solid (100 g, 54%). mp 165-170° C.

4-Chloro-2-(2-methoxy-phenyl)-7-methyl-quinazoline

To a mechanically stirred suspension of2-(2-methoxyphenyl)-7-methyl-3H-quinazolin-4-one (100 g, 0.37 mol) in 1L toluene was added diisopropyl ethylamine (100 mL), followed byphosphorus oxychloride (69 g, 0.45 mol). The reaction was then heated to80° C. for 4 h. The reaction mixture was distilled under reducedpressure to remove toluene, and the resulting residue was dissolved in2.2 L CH₂Cl₂. Ice water was added, and the pH was adjusted to 8-9 withsaturated aqueous sodium bicarbonate solution while maintaining thetemperature below 20° C. The resulting organic layer was separated andthe aqueous solution extracted with CH₂Cl₂, then the combined theorganic layers were dried over sodium sulfate and distilled underreduced pressure. The crude product was dissolved 2:1 CH₂Cl₂/hexane, andthe solution was passed through silica gel (2.5 kg, 60-120 mesh),followed by washing the silica bed with 2:1 CH₂Cl₂/hexane until theproduct eluted. The pure fractions were collected and combined, and thesolvent was removed under reduced pressure. Hexane (500 mL) was added,and the mixture was stirred and filtered to give4-chloro-2-(2-methoxy-phenyl)-7-methyl-quinazoline as a white tooff-white solid (77 g, 72%). mp 161-164° C. ¹H NMR (CDCl₃) δ 2.6 (s,3H), 3.9 (s, 3H), 6.9-7.2 (m, 2H), 7.4-7.6 (m, 2H), 7.7-8 (d, 2H), 8.2(d, 1H) ppm; ¹³C NMR (CDCl₃) δ 22.23, 56.06, 112.2, 120.26, 120.69,125.34, 127.94, 130.45, 131.08, 131.08. M/z (obs., [m+H]⁺)=285.

2-(7-Methyl-4-piperazin-1-yl-quinazolin-2-yl)-phenol

A stirring solution of 4-chloro-2-(2-methoxyphenyl)-7-methylquinazoline(91 g, 320 mmol) and CH₂Cl₂ (2.0 L) under an N₂ atmosphere was cooled to−30° C. Boron tribromide (957 mL, 957 mmol, 1.0 M in CH₂Cl₂) was addeddropwise over a period of 30 minutes at −30 to −40° C. The cooling bathwas removed, and the mixture was allowed to warm to 25° C. The mixturewas carefully poured into a stirring solution of saturated aqueousNaHCO₃ (4.0 L). The organic portion was separated, dried over MgSO₄, andevaporated to dryness. The resulting solid was suspended in CH₂Cl₂ (400mL) under an N₂ atmosphere, followed by the addition of triethylamine(64.8 g, 640 mmol). The solution was cooled to −10° C. A solution ofpiperazine (55.0 g, 640 mmol) in CH₂Cl₂ (400 mL) was added in a singleportion, and the solution was stirred at ambient temperature for 1 hour.The solution temperature rose to 23° C. upon addition of the piperazine.The solution was partitioned between CH₂Cl₂ and H₂O. The organic portionwas dried over MgSO₄ and evaporated to dryness. The residue was purifiedvia silica gel chromatography using 5% MeOH in CH₂Cl₂ to obtain a tansolid. The resulting solid was triturated with 1:1 Et₂O/hexanes toobtain a yellow solid which was vacuum dried to give2-(7-methyl-4-piperazin-1-yl-quinazolin-2-yl)-phenol as a light yellowsolid (93.0 g, 290 mmol, 91%). LC/MS: m/z 321.1 (M+H)⁺ at 2.34 min(10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)).

(R)-2-Hydroxy-1-(4-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperazin-1-yl)-4,4-dimethylpentan-1-one

Method A

2-(7-Methyl-4-(piperazin-1-yl)quinazolin-2-yl)phenol (50 mg, 0.16 mmol)was placed in a tube charged with a stir bar followed by(R)-2-hydroxy-4,4-dimethylpentanoic acid in 1 ml of DMF andtriethylamine (31.57 mg, 0.312 mmol), and the reaction was cooled to 0°C. HATU (71 mg, 0.187 mmol) was then added, and the reaction was allowedto stir at 0° C. for 10 minutes and then allowed to warm to roomtemperature. The reaction was complete after 40 minutes, filtered, andpurified by reverse phase HPLC to give the TFA salt of(R)-2-hydroxy-1-(4-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperazin-1-yl)-4,4-dimethylpentan-1-one.LC/MS: m/z 449.3 (M+H)⁺ at 2.75 min (10%-99% CH₃CN (0.035% TFA)/H₂O(0.05% TFA)).

Method B

2-(7-Methyl-4-(piperazin-1-yl)quinazolin-2-yl)phenol (250 mg, 0.74 mmol)was suspended in anhydrous DMF (5 mL) and cooled to 0° C. internaltemperature. Under an N₂ atmosphere, (R)-2-hydroxy-4,4-dimethylpentanoicacid (125.4 mg, 0.858 mmol) was added followed by triethylamine (0.218mL, 1.56 mmol). To this stirring solution was added HATU (356 mg, 0.936mmol). After the complete addition of HATU, the mixture was allowed towarm to 10° C. After 45 min the reaction was complete, and it wasquenched with an equal portion of ice water. A yellow precipitate formedwhich was collected by vacuum filtration and dissolved in CH₂Cl₂. Thissolution was desiccated with Na₂SO₄, filtered, and concentrated to givea viscous yellow-orange oil. The crude material was purified via silicagel chromatography using 88% CH₂Cl₂-hexanes (1:1) and 12% EtOAc toafford(R)-2-hydroxy-1-(4-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperazin-1-yl)-4,4-dimethylpentan-1-oneas a faint yellow foam (265 mg, 76%). LC/MS: m/z 449.3 (M+H)⁺ at 2.75min (10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)). ¹H NMR (400 MHz,DMSO-d6) δ 8.46 (dd, J=8.2, 1.8 Hz, 1H), 8.02 (d, J=8.5 Hz, 1H), 7.70(s, 1H), 7.41-7.37 (m, 2H), 6.97-6.93 (m, 2H), 4.89 (d, J=7.2 Hz, 1H),4.49-4.44 (m, 1H), 4.06-3.67 (m, 8), 2.52 (s, 3H), 1.56 (dd, J=14.3, 3.0Hz, 1H), 1.42 (dd, J=14.3, 8.8 Hz, 1H), 0.97 (s, 9H) ppm.

(R)-2-Hydroxy-1-(4-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperazin-1-yl)-4,4-dimethylpentan-1-onehydrochloride

(R)-2-Hydroxy-1-(4-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperazin-1-yl)-4,4-dimethylpentan-1-one(265 mg, 0.367 mmol) was dissolved in anhydrous CH₂Cl₂ (3 mL) followedby the addition of Et₂O (6 mL) under an N₂ atmosphere. A 2.0 M HClsolution in Et₂O (0.296 mL, 0.591 mmol) was added over a 1 minuteperiod. The reaction solution changed from a clear yellow solution to acreamy off white slurry. After complete addition of the HCl solution,the reaction was allowed to stir for an additional 10 minutes. Theproduct was collected by vacuum filtration, washed with 3 mL of Et₂O anddried under vacuum to obtain(R)-2-hydroxy-1-(4-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperazin-1-yl)-4,4-dimethylpentan-1-onehydrochloride as a white solid (261 mg, 91%). LC/MS: m/z 449.3 (M+H)⁺ at2.79 min (10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)). ¹H NMR (400 MHz,DMSO-d6) δ 8.33 (d, J=7.6 Hz, 1H), 8.07 (d, J=8.6 Hz, 1H), 7.75 (s, 1H),7.47-7.43 (m, 2H), 7.04-6.98 (m, 2H), 4.47-4.44 (m, 1H), 4.13-4.04 (m,4H), 3.91-3.68 (m, 4H), 2.54 (s, 3H), 1.57 (dd, J=14.3, 3.1 Hz, 1H),1.42 (dd, J=14.3, 8.8 Hz, 1H), 0.97 (s, 9H) ppm.

Example 102(R)-2-Hydroxy-1-(4-(2-(2-hydroxyphenyl)quinazolin-4-yl)piperazin-1-yl)-4-methylpentan-1-one

2-(2-Methoxyphenyl)quinazolin-4(3H)-one

Method A

To a cooled (0-5° C.) mixture of anthranilamide (350 g, 2.57 mol) andtriethylamine (286 g, 2.83 mol) in THF (2.5 L) was added dropwiseo-anisoyl chloride (437 g, 2.57 mol) while maintaining the temperaturebetween 0-20° C. The resulting suspension was stirred at roomtemperature overnight. The solvent was evaporated in vacuo, and theresidue was washed several times with water. The wet residue wassuspended in 2 M aq. NaOH (13 L), and the mixture was heated to reflux.After 20 minutes a clear solution was obtained. After 1 h of reflux theclear solution was cooled in an ice water bath and then acidified to pH6 with conc. aq. HCl. The suspension was filtered, and the residue waswashed thoroughly with water. The white solid was dried by azeotropicdistillation with toluene. 2-(2-Methoxyphenyl)quinazolin-4(3H)-one (567g) was obtained in 82%. ¹H-NMR (200 MHz, Me₂SO-d₆): δ 3.90 (s, 3 H),7.20 (m, 2 H), 7.60 (t, 2 H), 7.85 (m, 3 H), 8.20 (d, 1 H), 12.20 (s, 1H).

Method B

In a 2 L three-necked round-bottomed flask equipped with an overheadstirrer and reflux condenser, anthranilamide (20.0 g, 147 mmol) andpotassium carbonate (28.4 g, 206 mmol) were suspended in 1 L dry etherand heated to reflux. o-Anisoyl chloride (32.5 g, 191 mmol) was addedslowly to the refluxing mixture. After 3 hours at reflux, the reactionmixture was allowed to cool to room temperature, the ether was removedunder reduced pressure, and the resulting residue was filtered andwashed with water. The resulting solid was then suspended in 600 mL of5% aq. NaOH solution and boiled for one hour. The reaction was allowedto cool to room temperature, and it was neutralized with acetic acid,upon which 2-(2-methoxyphenyl)quinazolin-4(3H)-one was precipitated. Theproduct was collected by filtration, washed with water, and driedovernight in vacuo to yield 27 g (73%) of pure2-(2-methoxyphenyl)quinazolin-4(3H)-one. LC/MS: m/z 253.0 (M+H)⁺ at 3.22min (10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)). ¹H NMR (DMSO) 63.86(s, 3H), δ 7.09 (t, 1H), δ 7.18 (d, 1H), δ 7.53 (m, 2H), δ 7.70 (m, 2H),δ 7.80 (m, 1H), δ 8.14 (d, 1H), δ 12.11 (s, 1H) ppm; ¹³C NMR (DMSO) δ55.75, δ 111.86, δ 120.89, δ 120.97, δ 122.74, δ 125.75, δ 126.45, δ127.26, δ 130.41, δ 132.13, δ 134.32, δ 148.97, δ 152.48, δ157.12, δ161.35.

4-Chloro-2-2-(2-methoxyphenyl)quinazoline

A suspension of 2-(2-methoxyphenyl)quinazolin-4(3H)-one (567 g, 2.1 mol)in phosphoryl chloride (2 L, 21 mol) and a catalytic amount ofN,N-dimethyl aniline was brought to reflux. The reaction startedimmediately with the evolution of gas (HCl) upon the addition ofN,N-dimethyl aniline. After the production of gas had ceased the mixturewas cooled to room temperature. The excess POCl₃ was evaporated. Theresulting dark solution was cooled to room temperature and slowly pouredon ice and water, while maintaining the temperature below 5° C. The coldsuspension was extracted with dichloromethane. The extract was driedover sodium sulfate and filtered, and the solvent was removed in vacuo.The crude material was purified by column chromatography (silica gel,CH₂Cl₂). Yield: 189 g (33%) of 4-chloro-2-(2-methoxyphenyl) quinazoline.¹H-NMR (300 MHz, Me₂SO-d₆): δ 3.85 (s, 3 H), 7.15 (t, 1 H), 7.25 (d, 1H), 7.60 (t, 2 H), 7.70 (d, 1 H), 7.8 (d, 1 H), 7.9 (t, 1 H), 8.2 (d, 1H).

2-(4-Chloroquinazolin-2-yl)phenol

To a solution of 4-chloro-2-(2-methoxyphenyl)quinazoline (1.0 g, 3.7mmol) in 40 mL CH₂Cl₂ at −78° C. was added 5 equivalents of 1 M BBr₃dropwise. After complete addition the cooling bath was removed and thereaction was quenched with NaHCO₃ after 90 minutes. The product wasextracted twice with CH₂Cl₂, dried over Na₂SO₄, filtered, andconcentrated. Purification via silica gel chromatography using 60:40CH₂Cl₂: hexanes gave 2-(4-chloroquinazolin-2-yl)phenol (700 mg, 74%).LC/MS: m/z 257.1 (M+H)⁺ at 3.75 min (10%-99% CH₃CN (0.035% TFA)/H₂O(0.05% TFA)). ¹H NMR (400 MHz, DMSO-d6) δ 8.44 (m, 1H), 8.24 (m, 3H),7.89 (m, 1H), 7.49 (m, 1H), 7.05 (m, 2H) ppm.

2-(4-(piperazin-1-yl)quinazolin-2-yl)phenol

To a solution of 2-(4-chloroquinazolin-2-yl)phenol (2.0 g, 7.8 mmol) inCH₂Cl₂ at 0° C. was rapidly added a solution of piperazine (2.01 g, 23.4mmol) and triethylamine (2.17 mL, 15.6 mmol) in 10 mL CH₂Cl₂. Thereaction was warmed to room temperature and stirred for 5 hours. Thereaction was quenched with 25 mL of water and extracted with (3×15) mLof CH₂Cl₂. The organic layer was dried over Na₂SO₄, filtered, andconcentrated to afford 2-(4-(piperazin-1-yl)quinazolin-2-yl)phenol (1.98g, 83%). LC/MS: m/z 307.3 (M+H)⁺ at 1.47 min (10%-99% CH₃CN (0.035%TFA)/H₂O (0.05% TFA)). ¹H NMR (400 MHz, DMSO-d6) δ 8.43 (d, J=10.1 Hz,1H), 8.04 (d, J=8.3 Hz, 1H), 7.85 (m, 2H), 7.53 (m, 1H), 7.38 (m, 1H),6.95 (m, 2H), 3.85 (t, J=4.8 Hz, 4H), 2.94 (t, J=4.8 Hz, 4H) ppm.

(R)-2-Hydroxy-1-(4-(2-(2-hydroxyphenyl)quinazolin-4-yl)piperazin-1-yl)-4-methylpentan-1-one

To a solution of 2-(4-(piperazin-1-yl)quinazolin-2-yl)phenol (250 mg,0.82 mmol) in CH₂Cl₂ (6 mL) was added triethylamine (227 μL, 1.63 mmol)followed by the addition of (R)-2-hydroxy-4-methylpentanoic acid (140mg, 1.06 mmol) and HATU (403 mg, 1.06 mmol). The reaction mixture wasstirred at room temperature for 3 h and then quenched with H₂O. Theaqueous layer was extracted twice with CH₂Cl₂, dried over MgSO₄,filtered, and concentrated. Purification via silica gel chromatographyusing 0-10% EtOAc in 50:50 CH₂Cl₂:hexanes gave(R)-2-hydroxy-1-(4-(2-(2-hydroxyphenyl)quinazolin-4-yl)piperazin-1-yl)-4-methylpentan-1-one(265 mg, 77%). LC/MS: m/z 421.30 (M+H)⁺ at 2.57 min (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)). ¹H NMR (400 MHz, DMSO-d6) δ 8.47 (dd,J=8.3, 1.7 Hz, 1H), 8.12 (d, J=8.3 Hz, 1H) 7.88 (m, 2H), 7.57 (m, 1H),7.40 (m, 1H), 6.96 (m, 2H), 4.92 (d, J=7.2 Hz, 1H), 4.39 (m, 1H), 3.95(m, 4H), 3.76 (m, 4H), 1.80 (m, 1H), 1.43 (m, 2H), 0.92 (q, J=3.8 Hz,6H).

(R)-2-Hydroxy-1-(4-(2-(2-hydroxyphenyl)quinazolin-4-yl)piperazin-1-yl)-4-methylpentan-1-onehydrochloride

To a solution of(R)-2-hydroxy-1-(4-(2-(2-hydroxyphenyl)quinazolin-4-yl)piperazin-1-yl)-4-methylpentan-1-one(265 mg, 0.63 mmol) in CH₂Cl₂ (3 mL) under inert atmosphere was added 10mL of ether followed by the dropwise addition of 2 M HCl (0.315 mL, 0.63mmol). The reaction was stirred for 30 min before the formed precipitatewas filtered to afford(R)-2-hydroxy-1-(4-(2-(2-hydroxyphenyl)quinazolin-4-yl)piperazin-1-yl)-4-methylpentan-1-onehydrochloride (261 mg, 91%). LC/MS: m/z 421.3 (M+H)⁺ at 2.60 min(10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)). ¹H NMR (400 MHz, DMSO-d6)δ 8.28 (dd, J=7.9, 1.6 Hz, 1H), 8.19 (d, J=8.4 Hz, 1H), 7.96 (d, J=3.9Hz, 2H), 7.65 (m, 1H), 7.48 (m, 1H), 7.04 (m, 2H), 4.37 (m, 1H), 4.10(m, 4H), 3.80 (m, 4H), 1.77 (m, 1H), 1.41 (m, 2H), 0.91 (dd, J=6.6, 3.1Hz, 6H) ppm.

Example 103 (Benzo[d][1,3]dioxol-7-yl)methyl4-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperazine-1-carboxylate

(Benzo[d][1,3]dioxol-7-yl)methyl 1H-imidazole-1-carboxylate

A solution of (benzo[d][1,3]dioxol-7-yl)methanol (2 g, 13.14 mmol) anddi(1H-imidazol-1-yl)methanone (4.26 g, 26.28 mmol) in 20 mL CH₂Cl₂ washeated overnight at 50° C. The reaction was quenched with water,extracted with CH₂Cl₂, dried over Na₂SO₄, filtered, and concentrated.Purification via silica gel chromatography using 10-70% EtOAc in CH₂Cl₂gave (benzo[d][1,3]dioxol-7-yl)methyl 1H-imidazole-1-carboxylate (2.8 g,86%).

(Benzo[d][1,3]dioxol-7-yl)methyl4-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperazine-1-carboxylate

A solution of 2-(7-methyl-4-(piperazin-1-yl)quinazolin-2-yl)phenol (50mg, 0.16 mmol), (benzo[d][1,3]dioxol-7-yl)methyl1H-imidazole-1-carboxylate (78 mg, 0.32 mmol) and triethylamine (44.6μL, 0.32 mmol) in DMSO (500 μL) was heated in a microwave synthesizer at200° C. for 10 minutes. Purification using reverse phase HPLC (10%-99%CH₃CN (0.035% TFA)/H₂O (0.05% TFA)) gave(benzo[d][1,3]dioxol-7-yl)methyl4-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperazine-1-carboxylateas the TFA salt. LC/MS: m/z 499.3 (M+H)⁺ at 2.97 min (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)).

Example 104(R)-3-Hydroxy-4-(4-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperazin-1-yl)-N,N-dimethyl-4-oxobutanamide

(R)-3-(Methoxycarbonyl)-2-hydroxypropanoic acid

Methyl 2-((R)-2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)acetate (17.1 g, 90.9mmol) was stirred in a 1:1 mixture of THF: 1 M HCl (200 mL) for 1 h atroom temperature. After addition of NaCl to nearly saturate the aqueouslayer, the mixture was extracted with EtOAc, and the extracts were driedover Na₂SO₄ and concentrated to obtain(R)-3-(methoxycarbonyl)-2-hydroxypropanoic acid as an oil. ¹H NMR (400MHz, CDCl₃) δ 4.58-4.55 (m, 1H), 3.75 (s, 3H), 2.98-2.84 (m, 2H) ppm.

4-((R)-2-Hydroxy-3-methoxycarbonyl-propionyl)-piperazine-1-carboxylicacid benzyl ester

EDCI (3.6 g, 19 mmol) was added to a solution of(R)-3-(methoxycarbonyl)-2-hydroxypropanoic acid (2.8 g, 19 mmol) andHOBt (2.6 g, 19 mmol) in DMF (200 mL). After stirring this mixture for 5min, benzyl piperazine-1-carboxylate (4.2 g, 3.6 mL, 19 mmol) andtriethylamine (2.6 mL, 19 mmol) were added and stirred for 3 days atroom temperature. The reaction mixture was poured into water andextracted with EtOAc. After washing the organic layers with brine andwater, drying over Na₂SO₄ and concentrating, purification via silica gelchromatography using 0-10% MeOH/CH₂Cl₂ gave4-((R)-2-hydroxy-3-methoxycarbonyl-propionyl)-piperazine-1-carboxylicacid benzyl ester as an oil (2.19 g, 33%). ¹H NMR (400 MHz, CDCl₃) δ7.40-7.31 (m, 5H), 5.15 (s, 2H), 4.79-4.74 (m, 1H), 3.95 (d, J=8.0 Hz,1H), 3.79-3.74 (m, 1H), 3.74 (s, 3H), 3.71-3.44 (m, 7H), 2.62 (d, J=5.8Hz, 2H) ppm.

(R)-Methyl3-hydroxy-4-(4-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperazin-1-yl)-4-oxobutanoate

4-((R)-2-Hydroxy-3-methoxycarbonyl-propionyl)-piperazine-1-carboxylicacid benzyl ester (0.52 g, 1.5 mmol) and MeOH (15 mL) were stirred with10% Pd/C under an H₂ atmosphere at ambient pressure overnight. Afterfiltration and evaporation of the solvent the residue was taken up inCH₂Cl₂, and 2-(4-chloro-7-methylquinazolin-2-yl)phenol (0.40 g, 1.50mmol) plus triethylamine (0.41 mL, 3.00 mmol) were added. The reactionmixture was stirred at room temperature overnight, washed with water,dried over Na₂SO₄, and concentrated. Purification via silica gelchromatography using 0-10% MeOH/CH₂Cl₂ provided (R)-methyl3-hydroxy-4-(4-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperazin-1-yl)-4-oxobutanoate(0.38 g, 57%). LC/MS: m/z 451.1 (M+H)⁺ at 2.18 min (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)).

(R)-3-Hydroxy-4-{4-[2-(2-hydroxy-phenyl)-7-methyl-quinazolin-4-yl]-piperazin-1-yl}-4-oxo-butyricacid

LiOH.H₂O (19.8 mg, 0.47 mmol) was added to a solution of(R)-3-hydroxy-4-{4-[2-(2-hydroxy-phenyl)-7-methyl-quinazolin-4-yl]-piperazin-1-yl}-4-oxo-butyricacid methyl ester (71 mg, 0.16 mmol) in 2 mL THF:H₂O (1:1) and stirredat room temperature for 3 h. The reaction mixture was acidified with 1 MHCl and then extracted with EtOAc. After drying the organic layer overNa₂SO₄, it was concentrated and then purified via silica gelchromatography using 0-15% MeOH/CH₂Cl₂ to provide(R)-3-hydroxy-4-{4-[2-(2-hydroxy-phenyl)-7-methyl-quinazolin-4-yl]-piperazin-1-yl}-4-oxo-butyricacid (52 mg, 75%). LC/MS: m/z 437.3 (M+H)⁺ at 2.04 min (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)).

(R)-3-Hydroxy-4-(4-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperazin-1-yl)-N,N-dimethyl-4-oxobutanamide

(R)-3-Hydroxy-4-{4-[2-(2-hydroxy-phenyl)-7-methyl-quinazolin-4-yl]-piperazin-1-yl}-4-oxo-butyricacid (17 mg, 0.039 mmol) and HATU (16 mg, 0.043 mmol) were stirred inDMF (0.5 mL). After adding dimethylamine (2 M in THF, 0.10 mL, 0.19mmol), the reaction mixture was stirred at room temperature for 5 h.Purification via preparative reverse-phase HPLC (10%-99% CH₃CN (0.035%TFA)/H₂O (0.05% TFA)) gave(R)-3-hydroxy-4-(4-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperazin-1-yl)-N,N-dimethyl-4-oxobutanamideas the TFA salt. LC/MS: m/z 436.3 (M+H)⁺ at 1.94 min (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)).

Example 105(2-(Tetrahydro-2H-pyran-4-yl)-1-(4-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperazin-1-yl)ethanone

(2-(Tetrahydro-2H-pyran-4-yl)-1-(4-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperazin-1-yl)ethanone

To a solution of 2-(7-methyl-4-(piperazin-1-yl)quinazolin-2-yl)phenol(30 mg, 0.09 mmol) in DMF (1 mL) was added2-(tetrahydro-2H-pyran-4-yl)acetic acid (13.5 mg, 0.09 mmol) followed bythe addition of triethylamine (25 μL), then HATU (44 mg) at roomtemperature. The reaction was stirred overnight. Purification usingreverse phase HPLC (10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)) gave(2-(tetrahydro-2H-pyran-4-yl)-1-(4-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperazin-1-yl)ethanoneas the TFA salt. LC/MS: m/z 447.10 (M+H)⁺ at 2.32 min (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)).

Example 106(R)-2-Hydroxy-1-((R)-2-(hydroxymethyl)-4-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperazin-1-yl)-4-methylpentan-1-one

(R)-tert-Butyl2-((benzyloxy)methyl)-4-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperazine-1-carboxylate

To a solution of 2-(4-chloro-7-methylquinazolin-2-yl)phenol (450 mg,1.66 mmol) in 10 mL DMF was added a solution of (R)-tert-butyl2-((benzyloxy)methyl)piperazine-1-carboxylate (610 mg, 1.99 mmol) in DMFand triethylamine (0.46 mL). The reaction mixture was then refluxed at85° C. for 30 minutes, quenched with water, extracted twice with CH₂Cl₂,dried over Na₂SO₄, and concentrated to give (R)-tert-butyl2-((benzyloxy)methyl)-4-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperazine-1-carboxylate(760 mg, 85%). This material was used in the next step without furtherpurification. LC/MS: m/z 541.5 (M+H)⁺ at 3.37 min (10%-99% CH₃CN (0.035%TFA)/H₂O (0.05% TFA)).

2-(4-((R)-3-((Benzyloxy)methyl)piperazin-1-yl)-7-methylquinazolin-2-yl)phenol

To a solution of (R)-tert-butyl2-((benzyloxy)methyl)-4-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperazine-1-carboxylate(760 mg, 1.72 mmol) in 15 mL CH₂Cl₂ was added 10 mL of TFA. The reactionwas stirred for 1 hour. TFA was removed under vacuum and the reactionwas neutralized using a 1 M NaOH solution. The aqueous layer wasextracted twice with CH₂Cl₂, dried over Na₂SO₄, filtered, andconcentrated to obtain2-(4-((R)-3-((benzyloxy)methyl)piperazin-1-yl)-7-methylquinazolin-2-yl)phenol(570 mg, 92%). This material was used in the next step without furtherpurification. LC/MS: m/z 441.5 (M+H)⁺ at 2.44 min (10%-99% CH₃CN (0.035%TFA)/H₂O (0.05% TFA)).

(R)-1-((R)-2-((Benzyloxy)methyl)-4-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperazin-1-yl)-2-hydroxy-4-methylpentan-1-one

To a solution of2-(4-((R)-3-((benzyloxy)methyl)piperazin-1-yl)-7-methylquinazolin-2-yl)phenol(100 mg, 0.22 mmol) in DMF (1 mL) was added(R)-2-hydroxy-4-methylpentanoic acid (30 mg, 0.22 mmol) followed by theaddition of triethylamine (61 μL), then HATU (109 mg) at roomtemperature. The reaction was stirred overnight. Purification usingreverse phase HPLC (10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)) gave(R)-1-((R)-2-((benzyloxy)methyl)-4-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperazin-1-yl)-2-hydroxy-4-methylpentan-1-oneas the TFA salt. LC/MS: m/z 555.7 (M+H)⁺ at 3.13 min (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)).

(R)-2-Hydroxy-1-((R)-2-(hydroxymethyl)-4-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperazin-1-yl)-4-methylpentan-1-one

To a solution of(R)-1-((R)-2-((benzyloxy)methyl)-4-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperazin-1-yl)-2-hydroxy-4-methylpentan-1-onetrifluoroacetate salt (29.6 mg, 0.053 mmol) in ethanol was added Pd(OH)₂(188 mg), and the reaction was heated at 50° C. under H₂ atmosphere atambient pressure. The reaction was filtered, and purification usingreverse phase HPLC (10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)) gave(R)-2-hydroxy-1-((R)-2-(hydroxymethyl)-4-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperazin-1-yl)-4-methylpentan-1-oneas the TFA salt. LC/MS: m/z 465.50 (M+H)⁺ at 2.47 min (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)).

Example 107 (Pyridin-3-yl)methyl4-(2-(2-hydroxyphenyl)quinazolin-4-yl)piperazine-1-carboxylate

(Pyridin-3-yl)methyl 1H-imidazole-1-carboxylate

A solution of (pyridin-3-yl)methanol (2 g, 18.32 mmol) anddi(1H-imidazol-1-yl)methanone (5.94 g, 36.65 mmol) in 20 mL CH₂Cl₂ washeated overnight at 50° C. The reaction was quenched with water,extracted twice with CH₂Cl₂, dried over Na₂SO₄, filtered, andconcentrated. Purification via silica gel chromatography using 10-70%EtOAc in CH₂Cl₂ gave (pyridin-3-yl)methyl 1H-imidazole-1-carboxylate(3.1 g, 84%). LC/MS: m/z 204.1 (M+H)⁺ at 0.39 min (10%-99% CH₃CN (0.035%TFA)/H₂O (0.05% TFA)). ¹H NMR (400 MHz, CDCl₃) d 8.74 (d, J=1.9 Hz, 1H),8.68 (dd, J=4.8, 1.4 Hz, 1H), 8.16 (s, 1H), 7.81 (m, 1H), 7.44 (s, 1H),7.38 (m, 1H), 7.09 (s, 1H), 5.46 (s, 2H) ppm.

(Pyridin-3-yl)methyl4-(2-(2-hydroxyphenyl)quinazolin-4-yl)piperazine-1-carboxylate

A solution of 2-(4-(piperazin-1-yl)quinazolin-2-yl)phenol (50 mg, 0.16mmol), (pyridin-3-yl)methyl 1H-imidazole-1-carboxylate (67 mg, 0.32mmol) and triethylamine (44.6 μL, 0.32 mmol) in DMSO (500 μL) was heatedin a microwave synthesizer at 200° C. for 10 minutes. Purification usingreverse phase HPLC (10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)) gave(pyridin-3-yl)methyl4-(2-(2-hydroxyphenyl)quinazolin-4-yl)piperazine-1-carboxylate as theTFA salt. LC/MS: m/z 442.50 (M+H)⁺ at 1.97 min (10%-99% CH₃CN (0.035%TFA)/H₂O (0.05% TFA)).

Example 1082-Hydroxy-1-(4-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperazin-1-yl)-2-methylpropan-1-one

2-Hydroxy-1-(4-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperazin-1-yl)-2-methylpropan-1-one

A solution of 2-(7-methyl-4-(piperazin-1-yl)quinazolin-2-yl)phenol (70mg, 0.22 mmol) in DMF (0.5 mL) was added to 2-hydroxy-2-methylpropanoicacid (29.6 mg, 0.284 mmol). It was followed by the addition oftriethylamine (61 μL), then a solution of HATU (108 mg) in 0.5 mL DMF atroom temperature. The reaction was stirred overnight. Purification usingreverse phase HPLC (10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)) gave2-hydroxy-1-(4-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperazin-1-yl)-2-methylpropan-1-oneas the TFA salt. LC/MS: m/z 407.50 (M+H)⁺ at 2.21 min (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)).

Example 109(S)-3-Hydroxy-1-(4-(2-(2-hydroxyphenyl)quinazolin-4-yl)piperazin-1-yl)butan-1-one

(S)-3-Hydroxy-1-(4-(2-(2-hydroxyphenyl)quinazolin-4-yl)piperazin-1-yl)butan-1-one

A solution of 2-(4-(piperazin-1-yl)quinazolin-2-yl)phenol (70 mg, 0.23mmol) in DMF (0.5 mL) was added to (S)-3-hydroxybutanoic acid (31.0 mg,0.297 mmol). It was followed by the addition of triethylamine (63 μL),then a solution of HATU (113 mg) in 0.5 mL DMF at room temperature. Thereaction was stirred overnight. Purification using reverse phase HPLC(10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)) gave(S)-3-hydroxy-1-(4-(2-(2-hydroxyphenyl)quinazolin-4-yl)piperazin-1-yl)butan-1-oneas the TFA salt. LC/MS: m/z 393.1 (M+H)⁺ at 2.04 min (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)).

Example 1102-(Trifluoromethyl)-2-hydroxy-1-(4-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperazin-1-yl)propan-1-one

2-(Trifluoromethyl)-2-hydroxy-1-(4-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperazin-1-yl)propan-1-one

A solution of 2-(7-methyl-4-(piperazin-1-yl)quinazolin-2-yl)phenol (70mg, 0.22 mmol) in DMF (0.5 mL) was added to2-(trifluoromethyl)-2-hydroxypropanoic acid (45 mg, 0.284 mmol). It wasfollowed by the addition of triethylamine (61 μL), then a solution ofHATU (108 mg) in 0.5 mL DMF at room temperature. The reaction wasstirred overnight. Purification using reverse phase HPLC (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)) gave2-(trifluoromethyl)-2-hydroxy-1-(4-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperazin-1-yl)propan-1-oneas the TFA salt. LC/MS: m/z 461.1 (M+H)⁺ at 2.56 min (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)).

Example 111(R)-1-(4-(6-Fluoro-2-(2-hydroxyphenyl)quinazolin-4-yl)piperazin-1-yl)-2-hydroxy-4,4-dimethylpentan-1-one

(E)-N-(4-Fluorophenyl)-2-(hydroxyimino)acetamide

4-Fluoroaniline (58.2 g, 0.50 mol) was added slowly to 10% aqueous HClsolution. This suspension was added to a mixture of chloral hydrate (95g, 0.55 mol) and sodium sulfate (0.5 kg) in 750 mL water with mechanicalstirring. Hydroxylamine hydrochloride (116 g, 1.63 mol) dissolved inwater (250 mL) was added, and the resulting slurry was heated at 100° C.After this temperature was reached, the heating mantle was removedimmediately, and the solution was cooled to room temperature. The formedprecipitate was collected by filtration, washed with water (2×300 mL),and dried in a vacuum oven at 60° C. Yield: 78.2 g ofN-(4-fluorophenyl)-2-hydroxyiminoacetamide as an off-white solid.

5-Fluoroindoline-2,3-dione

Concentrated sulfuric acid (200 mL) was heated at 50° C., andN-(4-fluorophenyl)-2-hydroxyiminoacetamide was slowly added. The blacksolution was carefully heated at 90° C. At this temperature, some slightcooling was necessary to keep the temperature at 90° C. When no moreheat had developed, the reaction mixture was heated at 90° C. for anadditional half hour. The dark-red solution was cooled to roomtemperature and poured onto 3 L ice water and 1 L ethyl acetate withvigorous stirring. The layers were separated, and the aqueous layer wasextracted with ethyl acetate (1×1 L, 1×0.5 L). The combined organicextracts were dried over sodium sulfate, filtered, and evaporated todryness. Yield: 35.3 g (52%) of a dark red solid,5-fluoro-1H-indole-2,3-dione.

2-Amino-5-fluorobenzamide

5-Fluoro-1H-indole-2,3-dione (35.3 g, 213 mmol) was heated in aceticacid (300 mL), 1 mL concentrated sulfuric acid, and 22 mL 35% aq.hydrogen peroxide at 70° C. The solution was kept at that temperatureone and a half hours during which time a solid formed in the reactionmixture. After cooling to room temperature this solid was collected byfiltration and was washed three times with water. The wet solid wassuspended in 150 mL water, and 40 mL of a 25% aq. ammonia solution wasadded. This mixture was stirred at room temperature 3 days. The formedsolid was collected by filtration and was washed twice with water. Thesolid was dried by azeotropic distillation with toluene (3×100 mL) toyield 2-amino-5-fluorobenzamide (9.5 g). The combined filtrates wereextracted with ethyl acetate (2×100 mL). The combined extracts weredried over sodium sulfate, filtered, and evaporated to dryness to yield2-amino-5-fluorobenzamide (3.5 g) as an off-white solid. Both fractionswere combined for use in the next reaction step.

6-Fluoro-2-(2-methoxyphenyl)-3H-quinazolin-4-one

o-Anisoyl chloride (15.7 g, 92 mmol) was added dropwise to a solution of2-amino-5-fluorobenzamide (13.0 g, 84 mmol) and triethylamine (16 mL,110 mmol) in tetrahydrofuran (100 mL) cooled in an ice bath. Immediatelya precipitate started forming. Stirring of the solution was continuedfor 5 hours at room temperature. The formed precipitate was collected byfiltration and was washed twice with diethyl ether and dried at 50° C.in vacuo. The dried solid was suspended in 2 N aqueous sodium hydroxidesolution (250 mL) and heated at reflux until a clear solution wasobtained (3 hours). The reaction mixture was cooled to room temperatureand filtered. The filtrate was acidified to pH<1 with concentratedaqueous HCl. The formed precipitate was collected by filtration andwashed twice with water, twice with methanol, and twice with diethylether. The solid was dried in an oven at 45° C. to yield6-fluoro-2-(2-methoxyphenyl)-3H-quinazolin-4-one (18.2 g, 80%) as awhite solid.

4-Chloro-6-fluoro-2-(2-methoxyphenyl)quinazoline

A suspension of 6-fluoro-2-(2-methoxyphenyl)-3H-quinazolin-4-one (14.0g, 52 mmol), N,N-dimethylaniline (6.6 mL, 52 mmol), and phosphorusoxychloride (4.8 mL, 52 mmol) in benzene (100 mL) was heated at refluxuntil a clear, dark solution was obtained (1 hour). The reaction mixturewas cooled to room temperature, and the volume was reduced under reducedpressure. The black, oily residue was poured into 300 g of ice.Dichloromethane (600 mL) was added with vigorous stirring, and thetemperature was kept below 5° C. at all times. The pH was monitored, andaqueous 1 N sodium hydroxide was added until the pH was 10-11. Themixture was stirred for one hour at a temperature below 5° C., and thepH was kept between 10-11 by addition of 1 N aqueous sodium hydroxide.The layers were separated, and the organic layer was washed withice-cold 1 N aqueous sodium hydroxide (2×200 mL). Heptanes (300 mL) wereadded to the organic layer. This mixture was filtered through a shortplug of silica gel and eluted with dichloromethane/heptanes (2:1). Allfractions containing product were combined and evaporated to dryness.The residue was triturated with heptanes to yield4-chloro-6-fluoro-2-(2-methoxyphenyl)-quinazoline (11.5 g, 76%) as awhite solid.

2-(4-Chloro-6-fluoroquinazolin-2-yl)phenol

A solution of 4-chloro-6-fluoro-2-(2-methoxyphenyl)quinazoline (3.0 g,10.3 mmol) in CH₂Cl₂ (15 mL) was cooled to −78° C. Then, 1 M BBr₃ (51.95mL, 59.95 mmol) was added dropwise. The reaction was warmed to roomtemperature and was quenched with NaHCO₃ and extracted twice withCH₂Cl₂. The organic layer was dried over MgSO₄, filtered, andconcentrated. Purification via silica gel chromatography using 5-20%CH₂Cl₂ in hexanes gave 2-(4-chloro-6-fluoroquinazolin-2-yl)phenol (1.61g, 57%). LC/MS: m/z 275.1 (M+H)⁺ at 3.8 min (10%-99% CH₃CN (0.035%TFA)/H₂O (0.05% TFA)).

2-(6-Fluoro-4-(piperazin-1-yl)quinazolin-2-yl)phenol

To a stirring solution of 2-(4-chloro-6-fluoroquinazolin-2-yl)phenol(500 mg, 1.82 mmol) in CH₂Cl₂ (20 mL) at 0° C., under an N₂ atmospherewas rapidly added a solution of piperazine (0.263 g, 7.28 mmol) andtriethylamine (0.35 mL, 2.55 mmol) in CH₂Cl₂. The mixture was stirredfor 1 h and then quenched with H₂O, extracted twice with CH₂Cl₂, driedover Na₂SO₄, filtered, and concentrated. Purification via silica gelchromatography using 0-5% MeOH in CH₂Cl₂ gave2-(6-fluoro-4-(piperazin-1-yl)quinazolin-2-yl)phenol (400 mg, 68%).LC/MS: m/z 325.5 (M+H)⁺ at 2.12 min (10%-99% CH₃CN (0.035% TFA)/H₂O(0.05% TFA)). ¹H NMR (400 MHz, DMSO-d6) δ 8.42 (m, 1H), 7.97 (m, 1H),7.78 (m, 2H), 7.39 (m, 1H), 6.95 (m, 2H), 3.83 (t, J=4.9 Hz, 4H), 2.92(t, J=4.9 Hz, 4H) ppm.

(R)-1-(4-(6-Fluoro-2-(2-hydroxyphenyl)quinazolin-4-yl)piperazin-1-yl)-2-hydroxy-4,4-dimethylpentan-1-one

Method A

To a solution of 2-(6-fluoro-4-(piperazin-1-yl)quinazolin-2-yl)phenol(25 mg, 0.08 mmol) in DMF (1 mL) was added(R)-2-hydroxy-4,4-dimethylpentanoic acid (20.28 mg, 0.14 mmol) followedby the addition of triethylamine (25 μL), then HATU (44 mg) at roomtemperature. The reaction was stirred overnight. Purification usingreverse phase HPLC (10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA))-H₂O)gave(R)-1-(4-(6-fluoro-2-(2-hydroxyphenyl)quinazolin-4-yl)piperazin-1-yl)-2-hydroxy-4,4-dimethylpentan-1-oneas the TFA salt. LC/MS: m/z 453.52 (M+H)⁺ at 3.21 min (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)).

Method B

To a solution of 2-(6-fluoro-4-(piperazin-1-yl)quinazolin-2-yl)phenol(200 mg, 0.61 mmol) in CH₂Cl₂ (5 mL) was added triethylamine (170 μL,1.22 mmol) followed by the addition of(R)-2-hydroxy-4,4-dimethylpentanoic acid (116 mg, 0.79 mmol), then HATU(301 mg, 0.79 mmol). An additional 3 mL of CH₂Cl₂ was added, and thereaction was stirred for 3 h. After quenching with water, the mixturewas extracted twice with CH₂Cl₂. The organic phase was dried over MgSO₄and concentrated. Purification via silica gel chromatography using 0-10%EtOAc in 50:50 CH₂Cl₂:hexanes yielded(R)-1-(4-(6-fluoro-2-(2-hydroxyphenyl)quinazolin-4-yl)piperazin-1-yl)-2-hydroxy-4,4-dimethylpentan-1-one(240 mg, 86%). m/z: M+1 obs=453.5; t_(R)=3.19 minutes; ¹H NMR (400 MHz,DMSO-d6) d 8.46 (m, 1H), 8.01 (m, 1H), 7.84 (m, 2H), 7.40 (m, 1H), 6.96(m, 2H), 4.89 (d, J=7.1 Hz, 1H), 4.45 (m, 1H), 3.97 (m, 4H), 3.76 (m,4H), 1.56 (m, 1H), 1.42 (m, 1H), 0.97 (s, 9H) ppm.

(R)-1-(4-(6-Fluoro-2-(2-hydroxyphenyl)quinazolin-4-yl)piperazin-1-yl)-2-hydroxy-4,4-dimethylpentan-1-onehydrochloride

To a solution of(R)-1-(4-(6-fluoro-2-(2-hydroxyphenyl)quinazolin-4-yl)piperazin-1-yl)-2-hydroxy-4,4-dimethylpentan-1-one(230 mg, 0.51 mmol) in CH₂Cl₂ (3 mL) under an inert atmosphere was addeddropwise a 2 M HCl solution in ether (02.55 mL, 0.51 mmol). To it wasthen added ether (15 mL) which resulted in formation of a precipitatethat was allowed to stir for an hour. The product was collected byvacuum filtration and dried to afford(R)-1-(4-(6-fluoro-2-(2-hydroxyphenyl)quinazolin-4-yl)piperazin-1-yl)-2-hydroxy-4,4-dimethylpentan-1-onehydrochloride (230 mg, 92%). LCMS: m/z 453.5 (M+H)⁺ at 3.19 min (10%-99%CH₃CN (0.035% TFA)/H₂O (0.05% TFA)). ¹H NMR (400 MHz, DMSO-d6) δ 8.40(dd, J=7.8, 1.4 Hz, 1H), 8.04 (m, 1H), 7.88 (m, 2H), 7.43 (m, 1H), 6.99(m, 2H), 4.45 (dd, J=8.8, 3.0 Hz, 1H), 4.02 (m, 4H), 3.79 (m, 4H), 1.56(m, 1H), 1.42 (m, 1H), 0.97 (s, 9H) ppm.

Example 1124,4,4-Trifluoro-2-hydroxy-1-(4-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperazin-1-yl)butan-1-one

4,4,4-Trifluoro-2-hydroxy-1-(4-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperazin-1-yl)butan-1-one

2-(7-Methyl-4-(piperazin-1-yl)quinazolin-2-yl)phenol (87 mg, 0.27 mmol),4,4,4-trifluoro-2-hydroxybutanoic acid (43 mg, 0.27 mmol), HATU (0.12 g,0.33 mmol) and triethylamine (45 μL, 0.33 mmol) were stirred in DMF (3mL) at room temperature overnight. The mixture was diluted with waterand extracted with EtOAc. The combined organic layers were washed withbrine and water, dried over Na₂SO₄ and concentrated. Purification viasilica gel chromatography using 0-20% EtOAc in 1:1 CH₂Cl₂: hexanes gave4,4,4-trifluoro-2-hydroxy-1-(4-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperazin-1-yl)butan-1-oneas an off-white solid (86 mg, 66%). ¹H NMR (400 MHz, CDCl₃) d 8.46 (dd,J=8.0, 1.7 Hz, 1H), 7.77 (d, J=8.5 Hz, 1H), 7.70 (s, 1H), 7.41-7.37 (m,1H), 7.31 (dd, J=8.5, 1.5 Hz, 1H), 7.05-7.03 (m, 1H), 6.97-6.93 (m, 1H),4.80-4.75 (m, 1H), 4.07-3.68 (m, 9H), 2.56 (s, 3H), 2.50-2.39 (m, 2H)ppm; LC/MS: m/z 461.3 (M+H)⁺ at 2.49 min (10%-99% CH₃CN (0.035% TFA)/H₂O(0.05% TFA)).

Example 1132-Hydroxy-1-(4-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperazin-1-yl)-3-methylbutan-1-one

2-Hydroxy-1-(4-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperazin-1-yl)-3-methylbutan-1-one

Method A

Under an N₂ atmosphere, a mixture of2-(7-methyl-4-(piperazin-1-yl)quinazolin-2-yl)phenol (25 mg, 0.08 mmol),2-hydroxy-3-methylbutanoic acid (9 mg, 0.08 mmol), BOP (35 mg, 0.08mmol), triethylamine (22 μL, 0.16 mmol) and DMF (0.2 mL) was stirred atroom temperature for 1 hour. The reaction mixture was then purified viapreparative reverse phase HPLC using 10%99% CH₃CN (0.035% TFA)/H₂O(0.05% TFA) to give2-hydroxy-1-(4-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperazin-1-yl)-3-methylbutan-1-oneas the TFA salt. LC/MS: m/z 421.10 (M+H)⁺ at 2.76 min (10%99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)).

Method B

To a solution of 2-(7-methyl-4-(piperazin-1-yl)quinazolin-2-yl)phenol(250 mg, 0.78 mmol) in CH₂Cl₂ (6 mL) was added triethylamine (217 μL,1.56 mmol) followed by the addition of 2-hydroxy-3-methylbutanoic acid(120 mg, 1.0 mmol) and HATU (380 mg, 1.00 mmol). The reaction mixturewas stirred at room temperature for 3 h and then quenched with H₂O. Theaqueous layer was extracted with CH₂Cl₂, dried over MgSO₄, filtered, andconcentrated. Purification via silica gel chromatography using 0-10%EtOAc in 50:50 CH₂Cl₂:hexanes gave2-hydroxy-1-(4-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperazin-1-yl)-3-methylbutan-1-one(230 mg, 70%). LC/MS: m/z 421.3 (M+H)⁺ at 2.43 min (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)). ¹H NMR (400 MHz, DMSO-d6) d 8.45 (m, 1H),8.01 (d, J=8.5 Hz, 1H), 7.70 (s, 1H), 7.39 (m, 2H), 6.95 (m, 2H), 4.79(d, J=7.2 Hz, 1H), 4.11 (dd, J=7.0, 5.9 Hz, 1H), 3.87 (m, 8H), 2.52 (s,3H), 1.91 (m, 1H), 0.88 (dd, J=22.8, 6.7 Hz, 6H) ppm.

2-Hydroxy-1-(4-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperazin-1-yl)-3-methylbutan-1-onehydrochloride

To a solution of2-hydroxy-1-(4-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperazin-1-yl)-3-methylbutan-1-one(230 mg, 0.54 mmol) in CH₂Cl₂ (3 mL) under an inert atmosphere was addedether (12 mL) followed by the dropwise addition of 2 M HCl solution inether (0.27 mL, 0.54 mmol) which resulted in the formation of aprecipitate which was stirred for an hour and then collected by vacuumfiltration and dried to afford2-hydroxy-1-(4-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperazin-1-yl)-3-methylbutan-1-onehydrochloride (205 mg, 83%). LC/MS: m/z 421.3 (M+H)⁺ at 2.48 min(10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)). ¹H NMR (400 MHz, DMSO-d6)d 8.25 (d, J=7.9 Hz, 1H), 8.08 (d, J=8.5 Hz, 1H), 7.74 (s, 1H), 7.48 (t,J=6.6 Hz, 2H), 7.04 (m, 2H), 4.10 (m, 5H), 3.79 (m, 4H), 2.53 (s, 3H),1.90 (m, 1H), 0.87 (dd, J=16.3, 6.7 Hz, 6H) ppm.

Example 114 (Pyridin-4-yl)methyl4-(2-(2-fluoro-6-hydroxyphenyl)-7-methylquinazolin-4-yl)piperazine-1-carboxylate

N-(2-Cyano-5-methyl-phenyl)-2-fluoro-6-methoxy-benzamide

6-Fluoro-2-anisoic acid (110 g, 0.70 mol) was added in portions over 15minutes to a mixture of thionyl chloride (230 ml, 3.2 mol), toluene (200mL), and DMF (1 mL). The resulting mixture was stirred overnight at roomtemperature. The solution was evaporated to dryness and added dropwiseto an ice-bath cooled solution of 2-amino-4-methylbenzonitrile (92.5 g,0.70 mol) in pyridine (200 mL). The dropping funnel was rinsed with aminimal amount of acetonitrile. The resulting mixture was stirredovernight at room temperature under a nitrogen atmosphere and wassubsequently poured into 2 L ice water. The resulting slurry was stirredvigorously for 1 hour. The formed solid was collected by filtration andwas washed twice with water. The filter cake was dissolved in 2 Ldichloromethane, and this solution was washed with 1 N aq. HCl (400 mL)and with saturated aq. NaCl (400 mL), dried over sodium sulfate,filtered, and evaporated to dryness to giveN-(2-cyano-5-methylphenyl)-2-fluoro-6-methoxybenzamide (186 g, 93%) as abrownish solid. ¹H-NMR (CDCl₃, 200 MHz): δ 9.09 (s, 1H), 8.58 (s, 1H),7.59-7.42 (m, 2H), 7.09-7.02 (m, 1H), 6.94-6.83 (m, 2H), 4.11 (s, 3H),2.57 (s, 3H) ppm.

2-(2-Fluoro-6-methoxy-phenyl)-7-methyl-3H-quinazolin-4-one

To a suspension ofN-(2-cyano-5-methylphenyl)-2-fluoro-6-methoxybenzamide (31.5 g, 111mmol) in ethanol (626 mL) was added 6 M aqueous NaOH solution (205 mL).After 10 minutes, 30% aqueous H₂O₂ (60 mL) was added, forming a slurry.The reaction was heated to reflux for 18 h and cooled to roomtemperature. NaOH (22.2 g, 0.56 mol) and 30% aqueous H₂O₂ (26 mL) wereadded, and the reaction was heated to reflux for six hours. The reactioncooled to room temperature, 30% aqueous H₂O₂ (45 mL) was added, and thereaction was heated to reflux for 18 h. The reaction was cooled to roomtemperature, NaOH (10 g, 0.25 mol) and 30% aqueous H₂O₂ (70 mL) wereadded, and the reaction was heated to reflux for six hours. The reactionwas cooled to room temperature and poured over ice (800 mL). The pH wasadjusted to 3-4 by addition of conc. HCl solution, and the precipitatedoff-white solid was filtered and washed with water (3×40 mL). The solidwas dried under vacuum to provide2-(2-fluoro-6-methoxy-phenyl)-7-methyl-3H-quinazolin-4-one (28 g, 89%).

4-Chloro-2-(2-fluoro-6-methoxyphenyl)-7-methylquinazoline

Under an N₂ atmosphere,2-(2-fluoro-6-methoxyphenyl)-7-methylquinazolin-4(3H)-one (20 g, 70.35mmol) was suspended in benzene (300 mL), followed by the addition ofN,N-dimethylaniline (26.8 mL, 211.05 mmol), then POCl₃ (13.11 mL, 140.7mmol). The reaction was heated at reflux, and completion of productformation was observed after 1.5 h. After cooling to room temperature,the mixture was slowly poured over 1 liter of ice. The solution was thendiluted with CH₂Cl₂, and the pH was adjusted to 7 using a saturatedaqueous NaHCO₃ solution. The layers were partitioned, separated andextracted with CH₂Cl₂. All organic layers were combined, dried overNa₂SO₄, filtered, and concentrated to a dark oil. The crude material waspurified by silica gel chromatography using 75% CH₂Cl₂/25% hexanes toobtain 4-chloro-2-(2-fluoro-6-methoxyphenyl)-7-methylquinazoline as ayellow solid (18.82 g, 88%). LC/MS: m/z 302.9 (M+H)⁺ at 3.28 min(10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)). ¹H NMR (400 MHz, CDCl₃) d8.22 (d, J=8.5 Hz, 1H), 7.95 (s, 1H), 7.60 (dd, J=8.6, 1.5 Hz, 1H),7.42-7.40 (m, 1H), 6.86-6.84 (m, 2H), 3.81 (s, 3H), 2.64 (s, 3H) ppm.

2-(4-Chloro-7-methylquinazolin-2-yl)-3-fluorophenol

Under an N₂ atmosphere,4-chloro-2-(2-fluoro-6-methoxyphenyl)-methylquinazolin (7.0 g, 23.12mmol) was dissolved in CH₂Cl₂ (110 mL) and cooled to −50° C. internaltemperature using a dry ice/acetone bath. A 1.0 M solution of BBr₃ inCH₂Cl₂ (115.6 mL, 115.6 mmol) was added dropwise via an addition funnelwhile maintaining the internal temperature at −50° C. The reactionmixture was allowed to warm to 0° C., and the reaction was completeafter 1.5 h. It was then slowly quenched with saturated aqueous NaHCO₃solution to pH 7. After partitioning between CH₂Cl₂ and H₂O, the mixturewas separated and the aqueous layer was twice extracted with CH₂Cl₂. Thecombined organic layers were dried over Na₂SO₄, filtered, andconcentrated to a brown solid. Purification via silica gelchromatography using 75% CH₂Cl₂/25% hexanes gave2-(4-chloro-7-methylquinazolin-2-yl)-3-fluorophenol as a yellow solid(4.37 g, 66%). LC/MS: m/z 289.1 (M+H)⁺ at 3.71 min (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)). ¹H NMR (400 MHz, CDCl₃) d 8.22 (d, J=8.5Hz, 1H), 7.95 (s, 1H), 7.60 (dd, J=8.6, 1.5 Hz, 1H), 7.42-7.36 (m, 1H),6.86-6.82 (m, 2H), 3.81 (s, 3H), 2.64 (s, 3H) ppm.

3-Fluoro-2-(7-methyl-4-(piperazin-1-yl)quinazolin-2-yl)phenol

2-(4-Chloro-7-methylquinazolin-2-yl)-3-fluorophenol (4.37 g, 15.14 mmol)was suspended in CH₂Cl₂ (65 mL) under an N₂ atmosphere and placed intoan ice water bath. To this solution was added a solution of piperazine(4.00 g, 45.42 mmol) and triethylamine (4.2 mL, 30.28 mmol) in CH₂Cl₂(15 mL) in one portion. After stirring the reaction for 30 minutes, itwas partitioned between CH₂Cl₂ and H₂O and separated, and the aqueouslayer was extracted twice more with CH₂Cl₂. The organic phase was driedover Na₂SO₄, filtered, and concentrated to a bright yellow solid whichwas purified via silica gel chromatography using a 95%/5% mixture ofCH₂Cl₂/MeOH to afford3-fluoro-2-(7-methyl-4-(piperazin-1-yl)quinazolin-2-yl)phenol (4.32 g,85%) as a bright yellow solid. LC/MS: m/z 339.3 (M+H)⁺ at 1.80 min(10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)).

(Pyridin-4-yl)methyl 1H-imidazole-1-carboxylate

A solution of (pyridin-4-yl)methanol (2.0 g, 18.3 mmol) anddi(1H-imidazol-1-yl)methanone (5.94 g, 36.6 mmol) in 20 mL CH₂Cl₂ washeated overnight at 50° C. The reaction was quenched with water,extracted with CH₂Cl₂, dried over Na₂SO₄, filtered, and concentrated.Purification via silica gel chromatography using 10-70% EtOAc in CH₂Cl₂gave (pyridin-4-yl)methyl 1H-imidazole-1-carboxylate (3 g, 81%). LC/MS:m/z 204.3 (M+H)⁺ at 0.38 min (v). ¹H NMR (400 MHz, CDCl₃) d 8.69 (dd,J=4.4, 1.6 Hz, 2H), 8.20 (t, J=0.9 Hz, 1H), 7.47 (t, J=1.5 Hz, 1H), 7.34(dd, J=4.4, 1.6 Hz, 2H), 7.11 (dd, J=1.6, 0.8 Hz, 1H), 5.45 (s, 2H) ppm.

(Pyridin-4-yl)methyl4-(2-(2-fluoro-6-hydroxyphenyl)-7-methylquinazolin-4-yl)piperazine-1-carboxylate

3-Fluoro-2-(7-methyl-4-(piperazin-1-yl)quinazolin-2-yl)phenol (50 mg,0.15 mmol), (pyridin-4-yl)methyl 1H-imidazole-1-carboxylate (53 mg, 0.26mmol) and triethylamine (30.4 mg, 0.3 mmol) were added into a tube,followed by the addition of DMSO (1 mL). The mixture was stirred at roomtemperature for 18 h and then filtered, and purified via preparativereverse phase HPLC (10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)) giving(pyridin-4-yl)methyl4-(2-(2-fluoro-6-hydroxyphenyl)-7-methylquinazolin-4-yl)piperazine-1-carboxylate.LC/MS: m/z 474.30 (M+H)⁺ at 1.19 min (10%-99% CH₃CN (0.035% TFA)/H₂O(0.05% TFA)).

Example 1152-Ethyl-2-hydroxy-1-(4-(2-(2-hydroxyphenyl)quinazolin-4-yl)piperazin-1-yl)butan-1-one

2-Ethyl-2-hydroxy-1-(4-(2-(2-hydroxyphenyl)quinazolin-4-yl)piperazin-1-yl)butan-1-one

To a solution of 2-(4-(piperazin-1-yl)quinazolin-2-yl)phenol (70 mg,0.23 mmol) in DMF (0.5 mL) was added 2-ethyl-2-hydroxybutanoic acid(39.30 mg, 0.297 mmol). It was followed by the addition of triethylamine(63 μL), then a solution of HATU (113 mg) in 0.5 mL DMF at roomtemperature. The reaction was stirred overnight. Purification usingreverse phase HPLC (10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)) gave2-ethyl-2-hydroxy-1-(4-(2-(2-hydroxyphenyl)quinazolin-4-yl)piperazin-1-yl)butan-1-oneas the TFA salt. LC/MS: m/z 421.3 (M+H)⁺ at 2.51 min (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)).

Example 116 (Pyridin-4-yl)methyl4-(2-(2-hydroxyphenyl)quinazolin-4-yl)piperazine-1-carboxylate

(Pyridin-4-yl)methyl4-(2-(2-hydroxyphenyl)quinazolin-4-yl)piperazine-1-carboxylate

A solution of 2-(4-(piperazin-1-yl)quinazolin-2-yl)phenol (50 mg, 0.16mmol), (pyridin-4-yl)methyl 1H-imidazole-1-carboxylate (67 mg, 0.32mmol) and triethylamine (45 μL, 0.32 mmol) in DMSO (500 μL) was heatedin a microwave synthesizer at 200° C. for 10 minutes. Purification usingreverse phase HPLC (10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)) gave(pyridin-4-yl)methyl4-(2-(2-hydroxyphenyl)quinazolin-4-yl)piperazine-1-carboxylate as theTFA salt. LC/MS: m/z 442.50 (M+H)⁺ at 1.96 min (10%-99% CH₃CN (0.035%TFA)/H₂O (0.05% TFA)).

Example 117 (S)-Tetrahydrofuran-3-yl4-(6-fluoro-2-(2-hydroxyphenyl)quinazolin-4-yl)piperazine-1-carboxylate

(S)-Tetrahydrofuran-3-yl chloroformate

A stirred solution of (S)-tetrahydrofuran-3-ol (7.9 g, 90 mmol) inanhydrous CH₂Cl₂ (50 mL) under an N₂ atmosphere was cooled in an icebath, and a 20% solution of phosgene in toluene (134 mL, 270 mmol) wasslowly added. The reaction was allowed to warm to room temperatureovernight, and the solvent was removed under vacuum to afford(S)-tetrahydrofuran-3-yl chloroformate (12.1 g, 85%) as a clear liquid.¹H NMR (400 MHz, CDCl₃) d 5.42-5.39 (m, 1H), 4.01-3.84 (m, 4H),2.31-2.13 (m, 2H) ppm.

(S)-Tetrahydrofuran-3-yl4-(6-fluoro-2-(2-hydroxyphenyl)quinazolin-4-yl)piperazine-1-carboxylate

To a solution of 2-(6-fluoro-4-(piperazin-1-yl)quinazolin-2-yl)phenol(25 mg, 0.08 mmol) in DMF (1 mL) was added triethylamine (22 mL, 0.16mmol) followed by the dropwise addition of (S)-tetrahydrofuran-3-ylchloroformate (12 mg, 0.08 mmol) at 0° C. The reaction was completeimmediately after the addition of the chloroformate. Purification usingreverse phase HPLC (10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)) gave(S)-tetrahydrofuran-3-yl4-(6-fluoro-2-(2-hydroxyphenyl)quinazolin-4-yl)piperazine-1-carboxylateas the TFA salt. LC/MS: m/z 439.5 (M+H)⁺ at 2.79 min (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)).

Example 118(R)-2-Hydroxy-1-(4-(2-(2-hydroxyphenyl)quinazolin-4-yl)piperazin-1-yl)butan-1-one

(R)-2-Hydroxy-1-(4-(2-(2-hydroxyphenyl)quinazolin-4-yl)piperazin-1-yl)butan-1-one

Method A

A solution of 2-(4-(piperazin-1-yl)quinazolin-2-yl)phenol (70 mg, 0.23mmol) in DMF (0.5 mL) was added to (R)-2-hydroxybutanoic acid (31 mg,0.297 mmol), followed by the addition of triethylamine (63 μL), then asolution of HATU (113 mg) in 0.5 mL DMF at room temperature. Thereaction was stirred overnight. Purification using reverse phase HPLC(10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)) gave(R)-2-hydroxy-1-(4-(2-(2-hydroxyphenyl)quinazolin-4-yl)piperazin-1-yl)butan-1-oneas the TFA salt. LC/MS: m/z 393.30 (M+H)⁺ at 2.22 min (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)).

Method B

To a solution of 2-(4-(piperazin-1-yl)quinazolin-2-yl)phenol (250 mg,0.82 mmol) in CH₂Cl₂ (6 mL) was added triethylamine (227 μL, 1.63 mmol)followed by the addition of (R)-2-hydroxybutanoic acid (110 mg, 1.06mmol) and HATU (380 mg, 1.00 mmol). The reaction mixture was stirred atroom temperature for 3 h and then quenched with H₂O. The aqueous layerwas extracted twice with CH₂Cl₂, dried over MgSO₄, filtered, andconcentrated. Purification via silica gel chromatography using 0-10%EtOAc in 50:50 CH₂Cl₂:hexanes gave(R)-2-hydroxy-1-(4-(2-(2-hydroxyphenyl)quinazolin-4-yl)piperazin-1-yl)butan-1-one(280 mg, 88%). LC/MS: m/z 393.3 (M+H)⁺ at 2.17 min (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)). ¹H NMR (400 MHz, DMSO-d6) d 8.47 (m, 1H),8.12 (d, J=8.3 Hz, 1H), 7.89 (m, 2H), 7.57 (m, 1H), 7.40 (m, 1H), 6.96(m, 2H), 4.92 (d, J=7.1 Hz, 1H), 3.88 (m, 8H), 1.67 (m, 1H), 1.51 (m,1H), 0.91 (t, J=7.4 Hz, 3H) ppm.

(R)-2-Hydroxy-1-(4-(2-(2-hydroxyphenyl)quinazolin-4-yl)piperazin-1-yl)butan-1-onehydrochloride

To a solution of(R)-2-hydroxy-1-(4-(2-(2-hydroxyphenyl)quinazolin-4-yl)piperazin-1-yl)butan-1-one(280 mg, 0.71 mmol) in CH₂Cl₂ under an N₂ atmosphere was added a 2 M HClsolution in ether (0.355 mL, 0.71 mmol), followed by the addition ofether which resulted in the formation of precipitate which was stirredfor an hour and then filtered and dried to afford(R)-2-hydroxy-1-(4-(2-(2-hydroxyphenyl)quinazolin-4-yl)piperazin-1-yl)butan-1-onehydrochloride (272 mg, 90%). LC/MS: m/z 393.1 (M+H)⁺ at 2.23 min(10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)). ¹H NMR (400 MHz, DMSO-d6)d 8.27 (dd, J=7.9, 1.6 Hz, 1H), 8.19 (d, J=8.4 Hz, 1H), 7.96 (m, 2H),7.65 (m, 1H), 7.48 (m, 1H), 7.04 (m, 2H), 4.26 (dd, J=7.7, 4.8 Hz, 1H),4.03 (m, 4H), 3.79 (m, 5H), 1.65 (m, 1H), 1.50 (m, 1H), 0.90 (t, J=7.4Hz, 3H) ppm.

Example 119(S)-3-Hydroxymethyl-4-[2-(2-hydroxyphenyl)-7-methyl-quinazolin-4-yl]-piperazine-1-carboxylicacid tetrahydro-furan-3-yl ester

(S)-3-Hydroxymethyl-4-[2-(2-hydroxy-phenyl)-7-methyl-quinazolin-4-yl]-piperazine-1-carboxylicacid tetrahydro-furan-3-yl ester

To2-[4-(2-hydroxymethyl-piperazin-1-yl)-7-methyl-quinazolin-2-yl]-phenol(69.2 mg, 0.19 mmol) in 650 μL of CH₂Cl₂ at 0° C. was added(S)-tetrahydro-furan-3-ol-chloroformate (26.8 mg, 0.17 mmol), followedby triethylamine (30 μL, 0.22 mmol). The reaction mixture was stirredfor an hour and then diluted with 5 mL of CH₂Cl₂ and 5 mL of water, andthe organic layer was separated and dried over Na₂SO₄. The solvent wasremoved under reduced pressure, and the residue was subjected topurification using 30-100% EtOAc-hexanes to give the desired product.LC/MS: m/z 465.2 (M+H)⁺ at 2.5 min (10%-99% CH₃CN (0.035% TFA)/H₂O(0.05% TFA)).

Example 121(R)-2-Hydroxy-1-(4-(2-(2-hydroxyphenyl)quinazolin-4-yl)piperazin-1-yl)butan-1-one

(R)-2-Hydroxy-1-(4-(2-(2-hydroxyphenyl)quinazolin-4-yl)piperazin-1-yl)butan-1-one

A solution of 2-(4-(piperazin-1-yl)quinazolin-2-yl)phenol (70 mg, 0.23mmol) in DMF (0.5 mL) was added to (R)-2-hydroxybutanoic acid (31 mg,0.297 mmol). It was followed by the addition of triethylamine (63 μL),then a solution of HATU (113 mg) in 0.5 mL DMF at room temperature. Thereaction was stirred overnight. Purification using reverse phase HPLC(10-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)) gave(R)-2-hydroxy-1-(4-(2-(2-hydroxyphenyl)quinazolin-4-yl)piperazin-1-yl)butan-1-oneas the TFA salt. LC/MS: m/z 393.3 (M+H)⁺ at 2.21 min (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)).

Example 1222-Ethyl-2-hydroxy-1-(4-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperazin-1-yl)butan-1-one

2-Ethyl-2-hydroxy-1-(4-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperazin-1-yl)butan-1-one

A solution of 2-(7-methyl-4-(piperazin-1-yl)quinazolin-2-yl)phenol (70mg, 0.22 mmol) in DMF (0.5 mL) was added to 2-ethyl-2-hydroxybutanoicacid (37.5 mg, 0.284 mmol). It was followed by the addition oftriethylamine (61 μL), then a solution of HATU (108 mg) in 0.5 mL DMF atroom temperature. The reaction was stirred overnight. Purification usingreverse phase HPLC (10-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)) gave2-ethyl-2-hydroxy-1-(4-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperazin-1-yl)butan-1-oneas the TFA salt. LC/MS: m/z 435.3 (M+H)⁺ at 2.56 min (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)).

Example 1234-[4-((R)-2-Hydroxy-4-methyl-pentanoyl)-piperazin-1-yl]-2-(2-hydroxy-phenyl)-quinazoline-7-carboxylicacid

(R)-α-hydroxyisocaproic acid

To a cooled solution (0-5° C.) of D-leucine (200 g, 1.5 mol) in sulfuricacid (3 L, 1 M) was added dropwise a solution of sodium nitrite (240 g,3.5 mol) in water (1 L) while maintaining the temperature between 0-5°C. The reaction mixture was stirred at room temperature overnight. Thesolution was saturated with sodium chloride and extracted withtert-butyl methyl ether (3×). The combined organic layers were driedover Na₂SO₄ and filtered, and the solvent was removed in vacuo.(R)-α-hydroxyisocaproic acid was isolated as a white solid in a yield of67% (132 g).

(R)-1-(4-Benzyl-piperazin-1-yl)-2-hydroxy-4-methyl-pentan-1-one

To a cooled solution (0-5° C.) of (R)-α-hydroxyisocaproic acid (64.5 g,0.5 mol), 1-benzylpiperazine (88 g, 0.5 mol) and triethylamine (71 ml,0.5 mol) in CH₂Cl₂ (850 ml) was added in portions HOBt (68 g, 0.5 mol)and EDCI.HCl (96 g, 0.5 mol). The reaction mixture was stirred at roomtemperature overnight. The organic layer was washed with water (3×) andonce with brine, dried over Na₂SO₄, and filtered, and the solvent wasremoved in vacuo. Crude(R)-1-(4-benzyl-piperazin-1-yl)-2-hydroxy-4-methyl-pentan-1-one (132 g,91%) was used in the next step without further purification.

(R)-2-Hydroxy-4-methyl-1-piperazin-1-yl-pentan-1-one

To a solution of1-(4-benzyl-piperazin-1-yl)-2-hydroxy-4-methyl-pentan-1-one (132 g) inmethanol (1 L) was added Pd/C (20 g, 10% weight Pd on carbon). Thereaction mixture was stirred at room temperature overnight under anatmosphere of hydrogen. The reaction mixture was filtered throughCelite, and the solvent was removed in vacuo.(R)-2-Hydroxy-4-methyl-1-piperazin-1-yl-pentan-1-one was obtained as anoil (68 g, 74%).

1,2,3,4-Tetrahydro-2,4-dioxoquinazoline-7-carboxylic acid

To a stirring mixture of dimethyl 2-aminobenzene-1,4-dioate (10.5 g, 50mmol) and AcOH (3.4 mL, 60 mmol) in H₂O (200 mL) was added KOCN (8.1 g,100 mmol). The reaction mixture was heated at 100° C. for 3 h. Aftercooling in an ice bath, NaOH (24 g, 600 mmol) was slowly added to themixture and stirred for another 3 h at room temperature. Acidificationwith concentrated HCl resulted in formation of a yellow solid which wasfiltered, washed with water and dried under vacuum (8.3 g). NMR datashowed that the solid consisted of a 3:1 mixture of the desired1,2,3,4-tetrahydro-2,4-dioxoquinazoline-7-carboxylic acid and a sideproduct. This mixture was used in the next step without furtherpurification. ¹H NMR (400 MHz, DMSO-d6) d 7.98 (d, J=8.2 Hz, 1H), 7.75(d, J=1.2 Hz, 1H), 7.67 (dd, J=8.2, 1.4 Hz, 1H) ppm.

2,4-Dichloroquinazoline-7-carboxylic acid

A mixture of 1,2,3,4-tetrahydro-2,4-dioxoquinazoline-7-carboxylic acid(1.0 g, 4.9 mmol), POCl₃ (10 mL) and dimethylaniline (0.5 mL, 3.94 mmol)was heated at 90° C. for 3 h. After cooling and pouring the reactionmixture over ice, it was extracted with EtOAc. The combined extractswere washed with water, dried over Na₂SO₄ and concentrated. Purificationvia silica gel chromatography using 0-10% MeOH/CH₂Cl₂ provided2,4-dichloroquinazoline-7-carboxylic acid as a yellow solid (0.45 g,38%). ¹H NMR (400 MHz, DMSO-d6) d 8.46 (d, J=1.4 Hz, 1H), 8.42 (d, J=8.7Hz, 1H), 8.30 (dd, J=8.6, 1.5 Hz, 1H); LC/MS: m/z 243.1 (M+H)⁺ at 2.49min (10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)) ppm.

2-Chloro-4-[4-((R)-2-hydroxy-4-methyl-pentanoyl)-piperazin-1-yl]-quinazoline-7-carboxylicacid

To a solution of 2,4-dichloroquinazoline-7-carboxylic acid (0.45 g, 1.9mmol) in CH₂Cl₂ (20 mL) was added(R)-2-hydroxy-4-methyl-1-piperazin-1-yl-pentan-1-one (0.37 g, 1.9 mmol)and triethylamine (0.52 mL, 3.7 mmol). The reaction mixture was stirredovernight at room temperature and then purified via silica gelchromatography using 0-10% MeOH/CH₂Cl₂ to obtain2-chloro-4-[4-((R)-2-hydroxy-4-methyl-pentanoyl)-piperazin-1-yl]-quinazoline-7-carboxylicacid (0.58 g, 77%). LC/MS: m/z 407.3 (M+H)⁺ at 2.44 min (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)).

4-[4-((R)-2-Hydroxy-4-methyl-pentanoyl)-piperazin-1-yl]-2-(2-hydroxy-phenyl)-quinazoline-7-carboxylicacid

A mixture of2′-chloro-4-[4-((R)-hydroxy-4-methyl-pentanoyl)-piperazin-1-yl]-quinazoline-7-carboxylicacid (114 mg, 0.28 mmol),2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (88 μL, 0.42 mmol)Pd(dppf)Cl₂ (14 mg, 0.017 mmol) and K₂CO₃ (155 mg, 1.1 mmol) in DMF (4mL) and H₂O (1 mL) was heated in a sealed microwave vial at 170° C. for6 minutes. After filtration and evaporation of the solvents, the mixturewas purified using preparative HPLC (10-99% CH₃CN (0.035% TFA)/H₂O(0.05% TFA)) to give4-[4-((R)-2-hydroxy-4-methyl-pentanoyl)-piperazin-1-yl]-2-(2-hydroxy-phenyl)-quinazoline-7-carboxylicacid as the TFA salt. LC/MS: m/z 465.3 (M+H)⁺ at 2.50 min (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)).

Example 124(S)-2-Hydroxy-1-(4-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperazin-1-yl)butan-1-one

(S)-2-Hydroxy-1-(4-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperazin-1-yl)butan-1-one

Method A: A solution of2-(7-methyl-4-(piperazin-1-yl)quinazolin-2-yl)phenol (70 mg, 0.22 mmol)in DMF (0.5 mL) was added to (S)-2-hydroxybutanoic acid (31 mg, 0.297mmol). It was followed by the addition of triethylamine (63 μL), then asolution of HATU (113 mg) in 0.5 mL DMF at room temperature. Thereaction was stirred overnight. Purification using reverse phase HPLC(10-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)) gave(S)-2-hydroxy-1-(4-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperazin-1-yl)butan-1-oneas the TFA salt. LC/MS: m/z 407.5 (M+H)⁺ at 2.31 min (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)).

Method B: To a solution of2-(7-methyl-4-(piperazin-1-yl)quinazolin-2-yl)phenol (250 mg, 0.78 mmol)in CH₂Cl₂ (6 mL) was added triethylamine (217 μL, 1.56 mmol) followed bythe addition of (S)-2-hydroxybutanoic acid (105 mg, 1.0 mmol) and HATU(380 mg, 1.00 mmol). The reaction mixture was stirred at roomtemperature for 3 h and then quenched with H₂O. The aqueous layer wasextracted twice with CH₂Cl₂, dried over MgSO₄, filtered, andconcentrated. Purification via silica gel chromatography using 0-10%EtOAc in 50:50 CH₂Cl₂:hexanes gave(S)-2-hydroxy-1-(4-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperazin-1-yl)butan-1-one(300 mg, 95%). LC/MS: m/z 407.5 (M+H)⁺ at 2.31 min (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)). ¹H NMR (400 MHz, DMSO-d6) d 8.45 (m, 1H),8.01 (d, J=8.5 Hz, 1H), 7.70 (s, 1H), 7.39 (m, 2H), 6.95 (m, 2H), 4.92(d, J=7.0 Hz, 1H), 4.28 (q, J=6.5 Hz, 1H), 3.89 (m, 8H), 2.52 (s, 3H),1.67 (m, 1H), 1.51 (m, 1H), 0.91 (t, J=7.4 Hz, 3H) ppm.

(S)-2-Hydroxy-1-(4-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperazin-1-yl)butan-1-onehydrochloride

To a solution of(S)-2-hydroxy-1-(4-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperazin-1-yl)butan-1-one(300 mg, 0.73 mmol) in CH₂Cl₂ was added a 2 M HCl solution in ether(0.365 mL, 0.73 mmol), followed by the addition of ether until the saltprecipitated out, which was stirred for an hour, collected by vacuumfiltration and dried to afford(S)-2-hydroxy-1-(4-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperazin-1-yl)butan-1-onehydrochloride (270 mg, 84%). LC/MS: m/z 407.5 (M+H)⁺ at 2.31 min(10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)). ¹H NMR (400 MHz, DMSO-d6)d 8.26 (dd, J=7.9, 1.6 Hz, 1H), 8.07 (d, J=8.6 Hz, 1H), 7.73 (s, 1H),7.47 (m, 2H), 7.03 (m, 2H), 4.26 (dd, J=7.7, 4.8 Hz, 1H), 4.08 (m, 4H),3.79 (m, 4H), 2.53 (s, 3H), 1.65 (m, 1H), 1.50 (m, 1H), 0.89 (t, J=7.4Hz, 3H) ppm.

Example 125(R)-4-Fluoro-2-hydroxy-1-{4-[2-(2-hydroxy-phenyl)-7-methyl-quinazolin-4-yl]-piperazin-1-yl}-4-methyl-pentan-1-one

4-{4-[2-(2-Hydroxy-phenyl)-7-methyl-quinazolin-4-yl]-piperazin-1-yl}-4-oxo-but-2-enoicacid ethyl ester

To 2-(7-methyl-4-piperazin-1-yl-quinazolin-2-yl)-phenol (787 mg, 2.46mmol) in 8 mL of CH₂Cl₂ at room temperature was added sequentiallybut-2-enedioic acid monoethyl ester (531 mg, 3.69 mmol), triethylamine(686 μL, 4.92 mmol), BOP (1.63 g, 3.69 mmol). The reaction mixture wasstirred for 20 min and diluted with water and CH₂Cl₂. The organic layerwas separated and dried over Na₂SO₄, and the solvent was removed underreduced pressure to give an oil. The residue was subjected topurification by normal phase LC using 10-100% EtOAc-hexanes to give4-{4-[2-(2-Hydroxy-phenyl)-7-methyl-quinazolin-4-yl]-piperazin-1-yl}-4-oxo-but-2-enoicacid ethyl ester (1.00 g, 91% yield). LC/MS: m/z 447.3 (M+H)⁺ at 2.93min (10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)).

4-Hydroxy-1-{4-[2-(2-hydroxy-phenyl)-7-methyl-quinazolin-4-yl]-piperazin-1-yl}-4-methyl-pent-2-en-1-one

To4-{4-[2-(2-hydroxy-phenyl)-7-methyl-quinazolin-4-yl]-piperazin-1-yl}-4-oxo-but-2-enoicacid ethyl ester (655 mg, 1.47 mmol) in 2 mL of diethyl ether at −20° C.was added methyl magnesium bromide (8.4 mL, 11.7 mmol, 1.4 MTHF/Toluene), and the reaction mixture was allowed to warm to 0° C. over15 minutes The mixture was diluted with 10 mL of water and 15 mL ofCH₂Cl₂. The resulting emulsion was filtered, and the organic layer wasseparated and dried over Na₂SO₄. The solvent was removed under reducedpressure to give the alcohol. LC/MS: m/z 433.5 (M+H)⁺ at 2.56 min(10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)).

4-Fluoro-1-{4-[2-(2-hydroxy-phenyl)-7-methyl-quinazolin-4-yl]-piperazin-1-yl}-4-methyl-pent-2-en-1-one

To4-hydroxy-1-{4-[2-(2-hydroxy-phenyl)-7-methyl-quinazolin-4-yl]-piperazin-1-yl}-4-methyl-pent-2-en-1-one(330 mg, 0.76 mmol) at −78° C. in 3 mL of CH₂Cl₂ was added(diethylamino)sulfur trifluoride (185 mg, 1.15 mmol). The reactionmixture was stirred −78° C. for 2.5 h. The reaction mixture was dilutedwith 10 mL of water and 10 mL of CH₂Cl₂. The organic layer was separatedand dried over Na₂SO₄, and the solvent was removed under reducedpressure to give an oil. The residue was subjected to purification bynormal phase LC using 10-100% EtOAc-hexanes to give4-fluoro-1-{4-[2-(2-hydroxy-phenyl)-7-methyl-quinazolin-4-yl]-piperazin-1-yl}-4-methyl-pent-2-en-1-one(133 mg, 40% yield). LC/MS: m/z 435.4.3 (M+H)⁺ at 2.92 min (10%-99%CH₃CN (0.035% TFA)/H₂O (0.05% TFA)).

4-Fluoro-1-{4-[2-(2-hydroxy-phenyl)-7-methyl-quinazolin-4-yl]-piperazin-1-yl}-4-methyl-pentan-1-one

To4-fluoro-1-{4-[2-(2-hydroxy-phenyl)-7-methyl-quinazolin-4-yl]-piperazin-1-yl}-4-methyl-pent-2-en-1-one(228 mg) in 1.5 mL of methanol was added Pd/C (34 mg, 10% weight Pd oncarbon), and the reaction mixture was hydrogenated with a hydrogenballoon for 1 h. The resulting mixture was filtered through Celite, andthe solvent was removed to give4-fluoro-1-{4-[2-(2-hydroxy-phenyl)-7-methyl-quinazolin-4-yl]-piperazin-1-yl}-4-methyl-pentan-1-one.LC/MS: m/z 437.4 (M+H)⁺ at 2.86 min (10%/99% CH₃CN (0.035% TFA)/H₂O(0.05% TFA)).

(R)-4-Fluoro-2-hydroxy-1-{4-[2-(2-hydroxy-phenyl)-7-methyl-quinazolin-4-yl]-piperazin-1-yl}-4-methyl-pentan-1-one

To4-fluoro-1-{4-[2-(2-hydroxy-phenyl)-7-methyl-quinazolin-4-yl]-piperazin-1-yl}-4-methyl-pentan-1-one(225 mg, 0.53 mmol) in 500 μL of THF was added a 2.7 M LDA solution (0.8mL, 2.1 mmol) at −78° C. The resulting solution was stirred at −78° C.for 25 min, and then (1R)-(−)-(10-camphorsulfonyl)oxaziridine (361 mg,1.6 mmol) in 1.5 mL of THF was added slowly. The reaction mixture wasallowed to warm to −45° C. over 30 min, and then diluted with water andCH₂Cl₂. The organic layer was separated and dried over Na₂SO₄, and thesolvent was removed under reduced pressure. The residue was purified bypreparative reverse phase HPLC using 10-99% CH₃CN (0.035% TFA)/H₂O(0.05% TFA) to give(R)-4-fluoro-2-hydroxy-1-{4-[2-(2-hydroxy-phenyl)-7-methyl-quinazolin-4-yl]-piperazin-1-yl}-4-methylpentan-1-oneas the TFA salt. LC/MS: m/z 453.4 (M+H)⁺ at 2.79 min (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)).

Example 1263-Hydroxymethyl-4-[2-(2-hydroxy-phenyl)-7-methyl-quinazolin-4-yl]-piperazine-1-carboxylicacid phenyl ester

3-Hydroxymethyl-4-[2-(2-hydroxy-phenyl)-7-methyl-quinazolin-4-yl]-piperazine-1-carboxylicacid benzyl ester

To 2-(4-chloro-7-methyl-quinazolin-2-yl)-phenol (245 mg, 0.91 mmol) in3.0 mL of CH₂Cl₂ was added 3-hydroxymethyl-piperazine-1-carboxylic acidbenzyl ester (226 mg, 0.58 mmol) and triethylamine (190 μL, 1.37 mmol).The reaction mixture was stirred for 12 hours at room temperature, andadditional 3-hydroxymethyl-piperazine-1-carboxylic acid benzyl ester(100 mg, 0.4 mmol) and triethylamine (200 μL, 1.4 mmol) was added, andthe reaction mixture was heated at 40° C. for 6 h. The reaction mixturewas cooled, and diluted with 5 mL of CH₂Cl₂ and 5 mL of water, and theorganic layer was separated and dried over Na₂SO₄. The solvent wasremoved under reduced pressure, and the residue was purified by silicagel chromatography eluting with 20-85% EtOAc/hexanes to give3-hydroxymethyl-4-[2-(2-hydroxy-phenyl)-7-methyl-quinazolin-4-yl]-piperazine-1-carboxylicacid benzyl ester (216 mg, 65%). LCMS: m/z 485 (M+H)⁺ at 3.03 min(10%-99% CH₃CN/H₂O)

2-[4-(2-Hydroxymethyl-piperazin-1-yl)-7-methyl-quinazolin-2-yl]-phenol

To3-hydroxymethyl-4-[2-(2-hydroxy-phenyl)-7-methyl-quinazolin-4-yl]-piperazine-1-carboxylicacid benzyl ester (200 mg, 0.41 mmol) in 1.7 mL of methanol was added 39mg of Pd/C (10% wt Pd on carbon). The reaction mixture was stirred undera hydrogen atmosphere for 3 h. The mixture was filtered through Celite,and the solvent was removed to give2-[4-(2-hydroxymethyl-piperazin-1-yl)-7-methyl-quinazolin-2-yl]-phenol.LCMS: m/z 351.2 (M+H)⁺ at 2.11 min (10%-99% CH₃CN/H₂O).

3-Hydroxymethyl-4-[2-(2-hydroxy-phenyl)-7-methyl-quinazolin-4-yl]-piperazine-1-carboxylicacid phenyl ester

To2-[4-(2-hydroxymethyl-piperazin-1-yl)-7-methyl-quinazolin-2-yl]-phenol(31.9 mg, 0.091 mmol) in 300 μL of CH₂Cl₂ was added at 0° C.sequentially triethylamine (13.9 μL) and phenyl chloroformate (14.3 mg,0.091 mmol). The reaction mixture was stirred for 30 min and was warmedto room temperature and stirred for an additional 40 minutes At the endof this period, the solvent was removed, and the residue was dissolvedin DMSO and purified by preparative reverse phase HPLC using 1099% CH₃CN(0.035% TFA)/H₂O (0.05% TFA) as eluent to give3-hydroxymethyl-4-[2-(2-hydroxy-phenyl)-7-methyl-quinazolin-4-yl]-piperazine-1-carboxylicacid phenyl ester as the TFA salt. LC/MS: m/z 471.2 (M+H)⁺ at 2.93 min(10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)).

Example 1273-Cyclopentyl-1-(4-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperazin-1-yl)propan-1-one

3-Cyclopentyl-1-(4-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperazin-1-yl)propan-1-one

Method A

To 2-(7-methyl-4-(piperazin-1-yl)quinazolin-2-yl)phenol (53 mg, 0.17mmol) was added sequentially 3-cyclopentylpropanoyl chloride (29 mg,0.19 mmol) in 550 μL of CH₂Cl₂ and triethylamine (28 μL, 0.2 mmol). Themixture was stirred at 0° C. for 20 minutes. After adding H₂O andCH₂Cl₂, the phases were separated, and the organic layer was dried overNa₂SO₄ and concentrated under vacuum. Purification using preparativereverse phase HPLC (10-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)) gave3-cyclopentyl-1-(4-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperazin-1-yl)propan-1-oneas the TFA salt. LC/MS: m/z 445.5 (M+H)⁺ at 2.32 min (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)).

Method B

A solution of 2-(7-methyl-4-(piperazin-1-yl)quinazolin-2-yl)phenol (200mg, 0.62 mmol) in CH₂Cl₂ (6.0 mL) was stirred under an N₂ atmosphere.Then triethylamine (170 μL, 1.24 mmol) was added, and the reaction wascooled to −10 to −20° C. After adding 3-cyclopentylpropanoyl chloride(96 μL in 600 μL THF, 0.62 mmol), the reaction mixture was stirred for30 minutes. CH₂Cl₂ was added, and the organic phase was washed 2× withH₂O, dried over Na₂SO₄, and concentrated. Purification via silica gelchromatography using 0-10% EtOAc in 50:50 CH₂Cl₂: hexanes gave3-cyclopentyl-1-(4-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperazin-1-yl)propan-1-one(240 mg, 86%). LC/MS: m/z 445.50 (M+H)⁺ at 3.07 min (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)). ¹H NMR (400 MHz, DMSO-d6) d 8.45 (dd,J=8.2, 1.8 Hz, 1H), 8.00 (d, J=8.5 Hz, 1H), 7.69 (s, 1H), 7.39 (m, 2H),6.95 (m, 2H), 3.95 (dd, J=19.9, 5.6 Hz, 4H), 3.74 (m, 4H), 2.52 (s, 3H),2.38 (t, J=7.8 Hz, 2H), 1.76 (m, 3H), 1.55 (m, 6H), 1.16 (m, 2H) ppm.

3-Cyclopentyl-1-(4-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperazin-1-yl)propan-1-onehydrochloride

Under an N₂ atmosphere, a 1 M HCl solution in diethyl ether (0.54 mL,0.54 mmol) was added dropwise to a stirring solution of3-cyclopentyl-1-(4-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperazin-1-yl)propan-1-one(240 mg, 0.54 mmol) in CH₂Cl₂ (20 mL). After 10 min, ether was addeduntil a precipitate formed. The solid was collected by filtration anddried under vacuum to give3-cyclopentyl-1-(4-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperazin-1-yl)propan-1-onehydrochloride (230 mg, 88%). LC/MS: m/z 445.30 (M+H)⁺ at 3.08 min(10%-99% CH₃CN (0.035% TFA)4H₂O (0.05% TFA)). ¹H NMR (400 MHz, DMSO-d6)d 8.26 (d, J=8.0 Hz, 1H), 8.09 (d, J=8.5 Hz, 1H), 7.78 (s, 1H),7.50-7.46 (m, 2H), 7.09 (d, J=8.1 Hz, 1H), 7.04-7.00 (m, 1H), 4.15-4.11(m, 4H), 3.79-3.74 (m, 4H), 2.54 (s, 3H), 2.37 (t, J=7.7 Hz, 2H),1.82-1.74 (m, 3H), 1.60-1.45 (m, 6H), 1.12-1.08 (m, 2H) ppm.

Example 1281-(4-(6-Fluoro-2-(2-hydroxyphenyl)quinazolin-4-yl)piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-yl)ethanone

1-(4-(6-Fluoro-2-(2-hydroxyphenyl)quinazolin-4-yl)piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-yl)ethanone

2-(6-Fluoro-4-(piperazin-1-yl)quinazolin-2-yl)phenol (25 mg, 0.077mmol), 2-(tetrahydro-2H-pyran-4-yl)acetic acid (14.3 mg, 0.10 mmol),triethylamine (22 μL, 0.154 mmol), and HATU (38 mg, 0.10 mmol) werestirred in DMF (1 mL) overnight. Purification via reverse phase HPLC(10-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)) gave1-(4-(6-fluoro-2-(2-hydroxyphenyl)quinazolin-4-yl)piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-yl)ethanone,TFA salt. LC/MS: m/z 451.5 (M+H)⁺ at 2.60 min (10%-99% CH₃CN (0.035%TFA)/H₂O (0.05% TFA)).

Example 1292-Hydroxy-1-(4-(2-(2-hydroxyphenyl)quinazolin-4-yl)piperazin-1-yl)-2-methylbutan-1-one

2-Hydroxy-1-(4-(2-(2-hydroxyphenyl)quinazolin-4-yl)piperazin-1-yl)-2-methylbutan-1-one

A solution of 2-(4-(piperazin-1-yl)quinazolin-2-yl)phenol (70 mg, 0.23mmol) in DMF (0.5 mL) was added to 2-hydroxy-2-methylbutanoic acid (39.3mg, 0.297 mmol). It was followed by the addition of triethylamine (63μL) and a solution of HATU (113 mg) in 0.5 mL

DMF at room temperature. The reaction was stirred overnight.Purification using reverse phase HPLC (10-99% CH₃CN (0.035% TFA)/H₂O(0.05% TFA)) gave2-hydroxy-1-(4-(2-(2-hydroxyphenyl)quinazolin-4-yl)piperazin-1-yl)-2-methylbutan-1-oneas the TFA salt. LC/MS: m/z 407.5 (M+H)⁺ at 2.31 min (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)).

Example 130(R)-2-Hydroxy-1-{4-[2-(2-hydroxy-phenyl)-7-methyl-quinazolin-4-yl]-piperazin-1-yl}-3-phenylpropan-1-one

2-(7-Methyl-4-piperazin-1-yl-quinazolin-2-yl)-phenol, oxalate salt

To 2-(7-Methyl-4-piperazin-1-yl-quinazolin-2-yl)-phenol (30.6 g, 95.4mmol) in 900 mL CH₂Cl₂ was added oxalic acid (9.45 g, 105 mmol, 1.1 eq.)dissolved in 36 mL of methanol. The resulting cloudy solution wasstirred for 3 h and the resulting solid was filtered, washed withhexanes, and dried to give 29.3 g (75%) the oxalate salt of2-(7-Methyl-4-piperazin-1-yl-quinazolin-2-yl)-phenol. LC/MS: m/z 321.2(M+H)⁺ at 2.36 min (10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)).

2-(7-Methyl-4-piperazin-1-yl-quinazolin-2-yl)-phenol

To the oxalate salt of2-(7-methyl-4-piperazin-1-yl-quinazolin-2-yl)-phenol (1.32 g, 3.2 mmol)in 10 mL of CH₂Cl₂ was added triethylamine (2.2 mL, 16.0 mmol) at roomtemperature. The resulting mixture was stirred at room temperature for30 minutes. The reaction mixture was diluted with 10 mL of water, andthe organic layer was separated and dried over Na₂SO₄. The solvent wasremoved under reduced pressure to give2-(7-methyl-4-piperazin-1-yl-quinazolin-2-yl)-phenol as an oil which wasused without further purification.

(R)-2-Hydroxy-1-{4-[2-(2-hydroxy-phenyl)-7-methyl-quinazolin-4-yl]-piperazin-1-yl}-3-phenylpropan-1-one

To 2-(7-methyl-4-piperazin-1-yl-quinazolin-2-yl)-phenol (64 mg, 0.19mmol) in 600 μL of CH₂Cl₂ was added sequentially 3-(R)-phenyl lacticacid (35 mg, 0.21 mmol), BOP (93 mg, 0.21 mmol), and triethylamine (27.7μL, 0.2 mmol) at room temperature. The reaction mixture was stirred for1.5 h, diluted with 10 mL of methylene chloride, and washed with water(2×10 mL). The solvent was removed under reduced pressure to give an oilwhich was purified by normal phase LC (35%-100% EtOAc/hexanes) to give(R)-2-hydroxy-1-{4-[2-(2-hydroxy-phenyl)-7-methyl-quinazolin-4-yl]-piperazin-1-yl}-3-phenylpropan-1-one.LC/MS: m/z 469.3 (M+H)⁺ at 2.87 min (10%-99% CH₃CN (0.035% TFA)/H₂O(0.05% TFA)).

Example 131(S)-2-Hydroxy-1-{4-[2-(2-hydroxy-phenyl)-7-methyl-quinazolin-4-yl]-piperazin-1-yl}-3-phenylpropan-1-one

(S)-2-Hydroxy-1-{4-[2-(2-hydroxy-phenyl)-7-methyl-quinazolin-4-yl]-piperazin-1-yl}-3-phenylpropan-1-one

To 2-(7-methyl-4-piperazin-1-yl-quinazolin-2-yl)-phenol (79.9 mg, 0.25mmol) in 800 μL of CH₂Cl₂ was added sequentially 3-(S)-phenyl lacticacid (41.4 mg, 0.25 mmol), BOP (110 mg, 0.25 mmol), triethylamine (34.7μL, 0.25 mmol) at room temperature. The reaction mixture was stirred for1.5 h, diluted with 10 mL of methylene chloride, and washed with water(2×10 mL). The solvent was removed under reduced pressure to give an oilwhich was purified by normal phase LC (35%-100% EtOAc/hexanes) to give(S)-2-hydroxy-1-{4-[2-(2-hydroxy-phenyl)-7-methyl-quinazolin-4-yl]-piperazin-1-yl}3-phenylpropan-1-one.LC/MS: m/z 469.4 (M+H)⁺ at 2.88 min (10%-99% CH₃CN (0.035% TFA)/H₂O(0.05% TFA)).

Example 132 (Pyridin-3-yl)methyl4-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperazine-1-carboxylate

(Pyridin-3-yl)methyl 1H-imidazole-1-carboxylate

A solution of(pyridin-3-yl)methanol (2 g, 18.32 mmol) anddi(1H-imidazol-1-yl)methanone (5.94 g, 36.65 mmol) in 20 mL CH₂Cl₂ washeated overnight at 50° C. The reaction was washed with water, driedover MgSO₄, filtered, and concentrated. Purification via silica gelchromatography using 10-70% EtOAc in CH₂Cl₂ gave (pyridin-3-yl)methyl1H-imidazole-1-carboxylate (3 g, 81%). LC/MS: m/z 204.1 (M+H)⁺ at 0.39min (10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)). ¹H NMR (400 MHz,CDCl₃) δ 8.74 (d, J=1.9 Hz, 1H), 8.68 (dd, J=4.8, 1.4 Hz, 1H), 8.16 (s,1H), 7.81 (m, 1H), 7.44 (s, 1H), 7.38 (m, 1H), 7.09 (s, 1H), 5.46 (s,2H) ppm.

(Pyridin-3-yl)methyl4-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperazine-1-carboxylate

A solution of 2-(7-methyl-4-(piperazin-1-yl)quinazolin-2-yl)phenol (50mg, 0.16 mmol), (pyridin-3-yl)methyl 1H-imidazole-1-carboxylate (67 mg,0.32 mmol), and triethylamine (44.6 μL, 0.32 mmol) in DMSO (500 μL) washeated in a microwave synthesizer at 200° C. for 10 minutes.Purification using reverse phase HPLC (10-99% CH₃CN (0.035% TFA)/H₂O(0.05% TFA)) gave (pyridin-3-yl)methyl4-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperazine-1-carboxylateas the TFA salt. LC/MS: m/z 456.5 (M+H)⁺ at 2.04 min (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)).

Example 1331-(4-(2-(2-Hydroxyphenyl)-7-methylquinazolin-4-yl)piperazin-1-yl)-3-(pyridin-2-yl)propan-1-one

1-(4-(2-(2-Hydroxyphenyl)-7-methylquinazolin-4-yl)piperazin-1-yl)-3-(pyridin-2-yl)propan-1-one

A solution of 2-(7-methyl-4-(piperazin-1-yl)quinazolin-2-yl)phenol (30mg, 0.09 mmol) in DMF (0.5 mL) was added to 3-(pyridin-2-yl)propanoicacid (21.23 mg, 0.14 mmol). Triethylamine (25 μL) was added, followed bya solution of HATU (45 mg) in 0.5 mL DMF at room temperature. Thereaction was stirred overnight. Purification using reverse phase HPLC(10-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)) gave1-(4-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperazin-1-yl)-3-(pyridin-2-yl)propan-1-oneas the TFA salt. LC/MS: m/z 454.3 (M+H)⁺ at 1.94 min (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)).

Example 1342-Hydroxy-1-(4-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperazin-1-yl)pentan-1-one

2-Hydroxy-1-(4-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperazin-1-yl)pentan-1-one

A solution of 2-(7-methyl-4-(piperazin-1-yl)quinazolin-2-yl)phenol (70mg, 0.22 mmol) in DMF (0.5 mL) was added to 2-hydroxypentanoic acid(33.6 mg, 0.28 mmol). It was followed by the addition of triethylamine(61 μL), and a solution of HATU (108 mg) in 0.5 mL DMF at roomtemperature. The reaction was stirred overnight. Purification usingreverse phase HPLC (10-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)) gave2-hydroxy-1-(4-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperazin-1-yl)pentan-1-oneas the TFA salt. LC/MS: m/z 421.1 (M+H)⁺ at 2.46 min (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)).

Example 135(R)-1-(4-(2-(2-Fluoro-6-hydroxyphenyl)-7-methylquinazolin-4-yl)piperazin-1-yl)-2-hydroxy-4,4-dimethylpentan-1-one

(R)-1-(4-(2-(2-Fluoro-6-hydroxyphenyl)-7-methylquinazolin-4-yl)piperazin-1-yl)-2-hydroxy-4,4-dimethylpentan-1-one

Method A

3-Fluoro-2-(7-methyl-4-(piperazin-1-yl)quinazolin-2-yl)phenol (50 mg,0.15 mmol) was placed in a tube charged with a stir bar,(R)-2-hydroxy-4,4-dimethylpentanoic acid (26 mg, 0.18 mmol) in 1 ml ofDMF, and triethylamine (30 mg, 41 μL, 0.29 mmol), and the tube wascooled to 0° C. HATU (68 mg, 0.18 mmol) was added, and the reaction wasstirred at 0° C. for 10 minutes and then allowed to warm to roomtemperature. After 40 minutes, the reaction was filtered, and purifiedby reverse phase HPLC to give the TFA salt of(R)-1-(4-(2-(2-fluoro-6-hydroxyphenyl)-7-methylquinazolin-4-yl)piperazin-1-yl)-2-hydroxy-4,4-dimethylpentan-1-one.LC/MS: m/z 467.1 (M+H)⁺ at 2.59 min (10%-99% CH₃CN (0.035% TFA)/H₂O(0.05% TFA)).

Method B

3-Fluoro-2-(7-methyl-4-(piperazin-1-yl)quinazolin-2-yl)phenol (250 mg,0.74 mmol) was suspended in anhydrous DMF (5 mL) and cooled to 0° C.(internal temperature). Under an N₂ atmosphere,(R)-2-hydroxy-4,4-dimethylpentanoic acid (118.4 mg, 0.81 mmol) was addedfollowed by triethylamine (0.207 mL, 1.48 mmol). To this stirringsolution was added HATU (337 mg, 0.888 mmol). After the completeaddition of HATU, the mixture was allowed to warm to 10° C. After 45 minthe reaction was complete, and it was quenched with an equal portion ofice water. A yellow precipitate formed which was collected by vacuumfiltration, dissolved in CH₂Cl₂, and the CH₂Cl₂ solution was desiccatedwith Na₂SO₄, filtered, and concentrated to a viscous yellow-orange oil.The crude material was purified via silica gel chromatography using 70%CH₂Cl₂/hexanes (1:1) and 30% EtOAc to afford(R)-1-(4-(2-(2-fluoro-6-hydroxyphenyl)-7-methylquinazolin-4-yl)piperazin-1-yl)-2-hydroxy-4,4-dimethylpentan-1-oneas a yellow solid (171 mg, 50%). LC/MS: m/z 467.1 (M+H)⁺ at 2.63 min(10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)). ¹H NMR (400 MHz, DMSO-d6)δ 8.02 (d, J=8.6 Hz, 1H), 7.69 (s, 1H), 7.43 (dd, J=8.6, 1.5 Hz, 1H),7.37-7.32 (m, 1H), 6.80 (d, J=8.3 Hz, 1H), 6.76-6.71 (m, 1H), 4.87 (d,J=7.2 Hz, 1H), 4.47-4.43 (m, 1H), 4.01-3.75 (m, 8H), 2.52 (s, 3H), 1.55(dd, J=14.3, 3.0 Hz, 1H), 1.40 (dd, J=14.3, 8.8 Hz, 1H), 0.96 (s, 9H)ppm.

(R)-1-(4-(2-(2-Fluoro-6-hydroxyphenyl)-7-methylquinazolin-4-yl)piperazin-1-yl)-2-hydroxy-4,4-dimethylpentan-1-onehydrochloride

(R)-1-(4-(2-(2-Fluoro-6-hydroxyphenyl)-7-methylquinazolln-4-yl)piperazin-1-yl)-2-hydroxy-4,4-dimethylpentan-1-one(171 mg, 0.367 mmol) was dissolved in anhydrous CH₂Cl₂ (2 mL) followedby the addition of Et₂O (6 ml) under an N₂ atmosphere. A 2.0 M HClsolution in Et₂O (0.184 mL, 0.367 mmol) was added over a 1 minuteperiod. The reaction solution changed from a clear yellow solution to amilky white slurry. After complete addition of the HCl solution, thereaction was allowed to stir for an additional 10 minutes. The productwas collected by vacuum filtration and dried under vacuum to obtain(R)-1-(4-(2-(2-fluoro-6-hydroxyphenyl)-7-methylquinazolin-4-yl)piperazin-1-yl)-2-hydroxy-4,4-dimethylpentan-1-onehydrochloride as a light yellow solid (170 mg, 92%). LC/MS: m/z 467.3(M+H)⁺ at 2.60 min (10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)). ¹H NMR(400 MHz, DMSO-d6) d 8.17 (d, J=8.3 Hz, 1H), 7.66 (s, 1H), 7.56 (d,J=8.1 Hz, 1H), 7.48-7.43 (m, 1H), 6.92-6.83 (m, 2H), 4.44-4.41 (m, 1H),3.87-3.68 (m, 8H), 2.56 (s, 3H), 1.55 (dd, J=14.3, 3.0 Hz, 1H), 1.41(dd, J=14.3, 8.8 Hz, 1H), 0.96 (s, 9H) ppm.

Example 136(R)-1-(4-(2-(5-Fluoro-2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperazin-1-yl)-2-hydroxy-4-methylpentan-1-one

7-Methylquinazoline-2,4(1H,3H)-dione

To a suspension of 2-amino-4-methylbenzoic acid (58.9 g, 390 mmol) inwater (1.5 L) and glacial acetic acid (50 ml) was added dropwise asolution of potassium cyanate (80.5 g, 993 mmol) in water (300 ml).After completion of the addition and stirring at room temperature forhalf an hour, sodium hydroxide pellets (500 g) were added at such a ratethat the temperature was kept below 50° C. (with ice cooling). Duringthe addition the mixture became a clear solution for a short period, andupon continuation of the sodium hydroxide addition a cream precipitatestarted forming. The suspension was cooled to 0-5° C. and theprecipitate was collected by filtration and washed twice with water (150ml). The solid was poured in water (1 L) and was acidified withconcentrated aqueous HCl (30%, 150 ml). The solid was collected byfiltration and washed with water (150 ml) to yield7-methylquinazoline-2,4(1H,3H)-dione (57.0 g, 83%) after drying at 45°C. under vacuum.

2,4-Dichloro-7-methyl-quinazoline

7-Methylquinazoline-2,4(1H,3H)-dione (57.0 g, 324 mmol) was refluxedovernight in phosphorus oxychloride (250 ml) in a flask equipped with acalcium chloride guard tube. The clear, dark solution was cooled in anice bath and poured slowly into 2 L of ice water. The chocolate brownsolid was collected by filtration and washed with cold water (150 ml).The solid was dissolved in dichloromethane (500 ml) and filtered. Thefiltrate was washed with a saturated solution of NaCl, dried overNa₂SO₄, filtered, and evaporated to dryness yielding 43.0 g of crude2,4-dichloro-7-methyl-quinazoline. This material was dissolved in hotheptanes (0.5 L), and filtered while hot, and after cooling to roomtemperature, the precipitated solid was collected by filtration andwashed with pentane (100 ml). The solid was purified by chromatographyon silica gel with dichloromethane as the eluent to yield2,4-dichloro-7-methylquinazoline (28.5 g, 41%) as an off-white solid.

1-(4-benzyl-piperazin-1-yl)-2-(R)-hydroxy-4-methyl-pentan-1-one

(R)-α-hydroxyisocaproic acid (52.1 g, 0.394 mol) was added to a solutionof 1-benzylpiperazine (69.46 g, 0.394 mol) in CH₂Cl₂ (500 mL). Themixture was cooled in ice and Et₃N (57 mL, 0.5 mol) was added, followedby HOBt (53.25 g, 0.394 mol) and EDCI.HCl (76.0 g, 0.396 mol). Thereaction mixture was allowed to warm to room temperature overnight. Theorganic layer was washed with water (3×200 mL). The combined aqueouslayers were back-extracted with CH₂Cl₂ (3×25 mL). The combined organiclayers were washed with water (3×20 mL), dried over Na₂SO₄ andconcentrated to give1-(4-benzyl-piperazin-1-yl)-2-(R)-hydroxy-4-methyl-pentan-1-one as abrown oil (109 g, 0.375 mol, 95%). ¹H NMR (300 MHz, CDCl₃): d 7.35-7.24(m, 5H); 4.35 (dd, J=10 Hz, 2 Hz, 1H); 3.77-3.55 (m, 4H); 3.52 (s, 2H);3.36 (m, 2H); 4.45 (m, 4H); 1.97 (m, 1H); 1.47-1.38 (m, 1H); 1.29-1.21(m, 1H); 0.96 (d, J=6 Hz, 3H); 0.94 (d, J=6 Hz, 3H) ppm.

2-(R)-hydroxy-4-methyl-1-piperazin-1-yl-pentan-1-one

1-(4-benzyl-piperazin-1-yl)-2-(R)-hydroxy-4-methyl-pentan-1-one (109 g,0.375 mol) was dissolved in MeOH (0.5 L). Crystals formed upon additionof 10% Pd/C (16 grams). The mixture was hydrogenated under 1-4 barhydrogen pressure for two days. The catalyst was filtered off, thefiltrate was concentrated to give2-(R)-hydroxy-4-methyl-1-piperazin-1-yl-pentan-1-one as a brownish oil(72.7 g, 0.363 mol, 97%). ¹H NMR (300 MHz, CDCl₃): d 4.36 (dd, J=10 Hz,2 Hz, 1H); 3.76-3.66 (m, 1H); 3.62-3.52 (m, 1H); 3.37 (m, 2H); 2.99 (br.s, 2H); 2.89 (br. m, 4H); 1.96 (m, 1H); 1.48-1.38 (m, 1H); 1.29-1.21 (m,1H); 0.96 (d, J=9 Hz, 3H); 0.94 (d, J=9 Hz, 3H) ppm.

2-(R)-hydroxy-4-methyl-1-piperazin-1-yl-pentan-1-one oxalate

The above product was dissolved in ethanol (250 mL). Oxalic aciddihydrate (45.76 g, 0.363 mol) was added. The thick slurry was dilutedwith ethanol (250 mL) and stirred at room temperature for 3 hours. Thesalt was filtered off, washed with ethanol (2×100 mL) and dried in vacuoover drying pearls. Yield: 89.0 grams (0.307 mol, 84%) of2-(R)-hydroxy-4-methyl-1-piperazin-1-yl-pentan-1-one oxalate as a whitesolid. ¹H NMR (300 MHz, D₂O): d 4.68 (dd, J=3.3, 9.9 Hz, 1H); 3.95 (m,4H); 3.35 (m, 4H); 1.80 (m, 1H); 1.59 (m, 1H); 1.41 (m, 1H); 0.96 (d,J=6.5 Hz, 3H); 0.95 (d, J=6.5 Hz, 3H) ppm.

(R)-1-(4-(2-Chloro-7-methylquinazolin-4-yl)piperazin-1-yl)-2-hydroxy-4-methylpentan-1-one

To a solution of 2,4-dichloro-7-methylquinazoline (2.09 g, 9.83 mmol) inCH₂Cl₂ (10 mL) at 0° C. was added triethylamine (2.74 mL, 19.66 mmol),followed by the addition of(R)-2-hydroxy-4-methyl-1-(piperazin-1-yl)pentan-1-one (1.97 g, 9.83mmol). The reaction mixture was warmed to room temperature and stirredovernight. The mixture was then quenched with water and extracted twicewith CH₂Cl₂. The combined organic extracts were dried over MgSO₄,filtered, and concentrated to obtain(R)-1-(4-(2-chloro-7-methylquinazolin-4-yl)piperazin-1-yl)-2-hydroxy-4-methylpentan-1-one(6.78 g, 95%). LC/MS: m/z 377.5 (M+H)⁺ at 2.61 min (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)).

(R)-1-(4-(2-(5-Fluoro-2-methoxyphenyl)-7-methylquinazolin-4-yl)piperazin-1-yl)-2-hydroxy-4-methylpentan-1-one

(R)-1-(4-(2-Chloro-7-methylquinazolin-4-yl)piperazin-1-yl)-2-hydroxy-4-methylpentan-1-one(50 mg, 0.13 mmol), 5-fluoro-2-methoxyphenylboronic acid (27 mg, 0.16mmol), Pd(Ph₃P)₄ (9.2 mg, 0.008 mmol), and K₂CO₃ (37 mg, 0.27 mmol) wereplaced into a microwave tube charged with a stir bar. Acetonitrile (2mL) and H₂O (400 μL) were added, and the vessel was capped and heated at160° C. for 12 minutes in the microwave reactor. The reaction waspartitioned between EtOAc and H₂O, the layers were separated, and theaqueous layer was extracted once more with EtOAc. The organic extractswere combined, dried over Na₂SO₄, filtered, and concentrated to anorange gel. The reaction was purified by silica gel chromatography using10%-30% EtOAc in CH₂Cl₂/hexanes (2:1) to afford(R)-1-(4-(2-(5-fluoro-2-methoxyphenyl)-7-methylquinazolin-4-yl)piperazin-1-yl)-2-hydroxy-4-methylpentan-1-oneas a white foam (70%). LC/MS: m/z 467.30 (M+H)⁺ at 2.38 min (10%-99%CH₃CN (0.035% TFA)/H₂O (0.05% TFA)).

(R)-1-(4-(2-(5-Fluoro-2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperazin-1-yl)-2-hydroxy-4-methylpentan-1-one

(R)-1-(4-(2-(5-Fluoro-2-methoxyphenyl)-7-methylquinazolin-4-yl)piperazin-1-yl)-2-hydroxy-4-methylpentan-1-one(30 mg, 0.064 mmol) was dissolved in 1.5 mL anhydrous CH₂Cl₂. The flaskwas sealed with a septum, placed under an N₂ atmosphere and cooled to−78° C., and 0.32 mL of a 1 M solution of BBr₃ in CH₂Cl₂ was added over2 minutes. The reaction was allowed to warm to room temperature. After 5hours, the reaction was quenched with saturated aqueous NaHCO₃, andpartitioned between CH₂Cl₂ and water, and the layers were separated. Theorganic layer was dried over Na₂SO₄, filtered, and concentrated to a redoil. The reaction was purified by reverse phase HPLC to give(R)-1-(4-(2-(5-fluoro-2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperazin-1-yl)-2-hydroxy-4-methylpentan-1-oneas the TFA salt. LC/MS: m/z 453.30 (M+H)⁺ at 3.02 min (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)).

Example 137(S)-2-Hydroxy-1-(4-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperazin-1-yl)butan-1-one

(S)-2-Hydroxy-1-(4-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperazin-1-yl)butan-1-one

A solution of 2-(7-methyl-4-(piperazin-1-yl)quinazolin-2-yl)phenol (70mg, 0.22 mmol) in DMF (0.5 mL) was added to (S)-2-hydroxybutanoic acid(29.6 mg, 0.284 mmol). It was followed by the addition of triethylamine(61 μL) and a solution of HATU (108 mg) in 0.5 mL DMF at roomtemperature. The reaction was stirred overnight. Purification usingreverse phase HPLC (10-99% CH₃CN (0.035% TFA)H₂O (0.05% TFA)) gave(S)-2-hydroxy-1-(4-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperazin-1-yl)butan-1-oneas the TFA salt. LC/MS: m/z 407.3 (M+H)⁺ at 2.28 min (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)).

Example 138(S)-1-(4-(2-(2-Fluoro-6-hydroxyphenyl)-7-methylquinazolin-4-yl)piperazin-1-yl)-2-hydroxy-3,3-dimethylbutan-1-one

(S)-1-(4-(2-(2-Fluoro-6-hydroxyphenyl)-7-methylquinazolin-4-yl)piperazin-1-yl)-2-hydroxy-3,3-dimethylbutan-1-one

3-Fluoro-2-(7-methyl-4-(piperazin-1-yl)quinazolin-2-yl)phenol (30 mg,0.09 mmol), (S)-2-hydroxy-3,3-dimethylbutanoic acid (15.24 mg, 0.12mmol), triethylamine (25 μL, 0.18 mmol), and HATU (45.6 mg, 0.12 mmol)were stirred in DMF (1 mL) overnight. Purification via reverse phaseHPLC (10-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)) gave(S)-1-(4-(2-(2-fluoro-6-hydroxyphenyl)-7-methylquinazolin-4-yl)piperazin-1-yl)-2-hydroxy-3,3-dimethylbutan-1-oneas the TFA salt. LC/MS: m/z 453.3 (M+H)⁺ at 2.43 min (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)).

Example 139(S)-1-(4-(6-Fluoro-2-(2-hydroxyphenyl)quinazolin-4-yl)piperazin-3-yl)-2-hydroxy-3,3-dimethylbutan-1-one

(S)-1-(4-(6-Fluoro-2-(2-hydroxyphenyl)quinazolin-4-yl)piperazin-1-yl)-2-hydroxy-3,3-dimethylbutan-1-one

2-(6-Fluoro-4-(piperazin-1-yl)quinazolin-2-yl)phenol (30 mg, 0.09 mmol),(S)-2-hydroxy-3,3-dimethylbutanoic acid (16 mg, 0.12 mmol),triethylamine (25 mL, 0.18 mmol), and HATU (45.6 mg, 0.12 mmol) werestirred in DMF (1 mL) overnight. Purification via reverse phase HPLC(10-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)) gave(S)-1-(4-(6-fluoro-2-(2-hydroxyphenyl)quinazolin-4-yl)piperazin-1-yl)-2-hydroxy-3,3-dimethylbutan-1-oneas the TFA salt. LC/MS: m/z 439.5 (M+H)⁺ at 2.95 min (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)).

Example 140 (Benzo[d][1,3]dioxol-7-yl)methyl4-(2-(2-hydroxyphenyl)quinazolin-4-yl)piperazine-1-carboxylate

(Benzo[d][1,3]dioxol-7-yl)methyl 1H-imidazole-1-carboxylate

A solution of(benzo[d][1,3]dioxol-7-yl)methanol (2.0 g, 13.1 mmol) anddi(1H-imidazol-1-yl)methanone (4.26 g, 26.2 mmol) in 20 mL CH₂Cl₂ washeated overnight at 50° C. The reaction was quenched with water andextracted with CH₂Cl₂, and the combined layers were dried over MgSO₄,filtered, and concentrated. Purification via silica gel chromatographyusing 10-70% EtOAc in CH₂Cl₂ gave (benzo[d][1,3]dioxol-7-yl)methyl1H-imidazole-1-carboxylate (2.8 g, 86%). ¹H NMR (400 MHz, CDCl₃) δ 8.15(t, J=0.9 Hz, 1H), 7.44 (t, J=1.4 Hz, 1H), 7.07 (dd, J=1.6, 0.8 Hz, 1H),6.95 (m, 2H), 6.84 (m, 1H), 6.01 (s, 2H), 5.33 (s, 2H) ppm.

(Benzo[d][1,3]dioxol-7-yl)methyl4-(2-2-hydroxyphenyl)quinazolin-4-yl)piperazine-1-carboxylate

A solution of 2-(4-(piperazin-1-yl)quinazolin-2-yl)phenol (50 mg, 0.16mmol), (benzo[d][1,3]dioxol-7-yl)methyl 1H-imidazole-1-carboxylate (78mg, 0.32 mmol), and triethylamine (44.6 μL, 0.32 mmol) in DMSO (500 μL)was heated in a microwave synthesizer at 200° C. for 10 minutes.Purification using reverse phase HPLC (10-99% CH₃CN (0.035% TFA)/H₂O(0.05% TFA)) gave (benzo[d][1,3]dioxol-7-yl)methyl4-(2-(2-hydroxyphenyl)quinazolin-4-yl)piperazine-1-carboxylate as theTFA salt. LC/MS: m/z 485.5 (M+H)⁺ at 2.94 min (10%-99% CH₃CN (0.035%TFA)/H₂O (0.05% TFA)).

Example 141(S)-2-Hydroxy-1-(4-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperazin-1-yl)-3-(1H-imidazol-5-yl)propan-1-one

(S)-2-Hydroxy-1-(4-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperazin-1-yl)-3-(1H-imidazol-5-yl)propan-1-one

2-(7-Methyl-4-(piperazin-1-yl)quinazolin-2-yl)phenol (87 mg, 0.27 mmol),(S)-2-hydroxy-3-(1H-imidazol-5-yl)propanoic acid (64 mg, 0.41 mmol),triethylamine (76 μL, 0.54 mmol), and BOP (180 mg, 0.41 mmol) in 1 mL ofCH₂Cl₂ were stirred at room temperature for 1.5 h. The reaction mixturewas diluted with H₂O and CH₂Cl₂. The organic layer was dried over Na₂SO₄and concentrated. Purification using 1-15% MeOH in CH₂Cl₂ gave(S)-2-hydroxy-1-(4-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperazin-1-yl)-3-(1H-imidazol-5-yl)propan-1-one.LC/MS: m/z 459.3 (M+H)⁺ at 2.13 min (10%-99% CH₃CN (0.035% TFA)/H₂O(0.05% TFA)).

Example 1424-[4-((R)-2-Hydroxy-4-methyl-pentanoyl)-piperazin-1-yl]-2-(2-hydroxy-phenyl)-quinazoline-6-carbonitrile

6-Bromo-1H-benzo[d][1,3]oxazine-2,4-dione

Bromine (35 mL, 660 mmol) was added dropwise to a suspension of isatoicanhydride (100 g, 610 mmol) in 1.6 L water at 50° C. This temperaturewas maintained for an additional 2 hours. After cooling the solution toroom temperature, the solid was filtered and washed twice with water andtwice with acetone, yielding 125.6 g (85%)6-bromo-1H-benzo[d][1,3]oxazine-2,4-dione as a pink solid.

2-Amino-5-bromo-benzamide

6-Bromo-1H-benzo[d][1,3]oxazine-2,4-dione (56.0 g, 230 mmol) wassuspended in 1 N aq. NH₄OH (600 mL, 2.6 equivalents), and the suspensionwas stirred 3 d at room temperature. After filtration, the collectedsolid was washed with water and subsequently dissolved intetrahydrofuran. This solution was filtered, evaporated to dryness, anddried by repeated azeotropic distillation with toluene. The solid wassuspended in CH₂Cl₂, filtered, and washed once with CH₂Cl₂ yielding 35.4g (71.2%) of 2-amino-5-bromo-benzamide.

2-(o-Anisoyl)-amino-5-bromo-benzamide

To a solution of 2-amino-5-bromo-benzamide (29.2 g, 136 mmol) andtriethylamine (25.0 mL, 173 mmol) in THF (500 mL) was added dropwiseo-anisoyl chloride (24.0 g, 140 mmol). Stirring at room temperature wascontinued for 3 h, after which the formed precipitate was filtered andwashed once with THF and twice with dichloromethane yielding2-(o-anisoyl)-amino-5-bromo-benzamide (51.4 g, 84%) with 1 equivalent oftriethylamine hydrochloride.

6-Bromo-2-(2-methoxy-phenyl)-3H-quinazolin-4-one

2-(o-Anisoyl)-amino-5-bromo-benzamide (50.8 g, 105 mmol) was suspendedin 2 N aq. NaOH (500 mL) and heated to reflux until a clear solution wasobtained (1.5 h). The solution was cooled to room temperature andfiltered. The filtrate was acidified with conc. aq. HCl, and theprecipitate formed was filtered and washed twice with 1 N aq. HCl andtwice with water. The solid was dried by repeated azeotropicdistillation with toluene yielding6-bromo-2-(2-methoxy-phenyl)-3H-quinazolin-4-one (31.3 g, 91%).

6-Bromo-4-chloro-2-(2-methoxyphenyl)quinazoline

Method A

6-Bromo-2-(2-methoxyphenyl)quinazolin-4(3H)-one (674 mg, 2.0 mmol),POCl₃ (624 mg, 4 mmol), and N,N-dimethylaniline (740 mg, 6.1 mmol) weredissolved in benzene (12 mL) and refluxed for 3 h. The reaction mixturewas diluted with EtOAc, and the organic phase was washed with aqueoussaturated NaHCO₃ (1×) and H₂O (2×), dried over Na₂SO₄, and concentrated.Purification via silica gel chromatography using 0-5% EtOAc inCH₂Cl₂/hexanes (1:1) gave6-bromo-4-chloro-2-(2-methoxyphenyl)quinazoline. LC/MS: m/z 348.9 (M+H)⁺at 3.66 min (10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)).

Method B

6-Bromo-2-(2-methoxyphenyl)quinazolin-4(3H)-one (0.31 g, 0.94 mmol),POCl₃ (86 μL, 0.94 mmol), and N,N-dimethylaniline (180 μL, 1.4 mmol)were refluxed in dry toluene for 3 h. Additional POCl₃ (0.94 mmol) wasadded, and the reaction was refluxed for one additional hour. Thereaction mixture was diluted with EtOAc and water. The aqueous layer wasmade basic with NaHCO₃, and the layers were separated. After the organicphase was washed with water, dried over Na₂SO₄ and concentrated,purification via silica gel chromatography using 0-50% EtOAc in 1:1hexanes:CH₂Cl₂ gave 6-bromo-4-chloro-2-(2-methoxyphenyl)quinazoline as ayellow solid (144 mg, 44%). ¹H NMR (400 MHz, CDCl₃) d 8.45-8.45 (m, 1H),8.04-7.99 (m, 2H), 7.82 (dd, J=7.6, 1.7 Hz, 1H), 7.49-7.45 (m, 1H),7.12-7.08 (m, 1H), 7.06 (d, J=8.4 Hz, 1H), 3.90 (s, 3H) ppm; LC/MS: m/z350.9 (M+H)⁺ at 3.56 min (10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)).

2-(6-Bromo-4-chloroquinazolin-2-yl)phenol

Method A

6-Bromo-4-chloro-2-(2-methoxyphenyl)quinazoline (393 mg, 1.12 mmol) wasdissolved in CH₂Cl₂ (3 mL), and the flask was flushed with N₂. Aftercooling the reaction mixture to −78° C., 1 M BBr₃ in CH₂Cl₂ (3.37 mL,3.37 mmol) was added dropwise, then the reaction was slowly warmed toroom temperature and stirred for 2 h. After quenching the mixture withsaturated aqueous NaHCO₃ (1×), it was transferred into a separatoryfunnel with CH₂Cl₂. The organic layer was washed with H₂O (2×), driedover Na₂SO₄, and concentrated. Purification via silica gelchromatography using 0-5% EtOAc and CH₂Cl₂:hexanes (1:1) gave2-(6-bromo-4-chloroquinazolin-2-yl)phenol (229 mg, 61%). LC/MS: m/z335.30 (M+H)⁺ at 4.18 min (10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)).

Method B

A solution of 6-bromo-4-chloro-2-(2-methoxyphenyl)quinazoline (0.14 g,0.4 mmol) in CH₂Cl₂ (mL) was cooled in a dry ice/acetone bath. Asolution of 1.0 M BBr₃ in CH₂Cl₂ (1.2 mL, 1.2 mmol) was slowly added.The cooling bath was removed, and the reaction was stirred at roomtemperature for 2 h. The reaction was diluted with CH₂Cl₂ and made basicwith a saturated NaHCO₃ solution. The organic layer was separated,washed with water, dried over Na₂SO₄, and evaporated to give6-bromo-4-chloro-2-(2-hydroxyphenyl)quinazoline (0.15 g).

(R)-1-(4-(6-Bromo-2-(2-hydroxyphenyl)quinazolin-4-yl)piperazin-1-yl)-2-hydroxy-4-methylpentan-1-one

Method A

To a solution of 2-(6-bromo-4-chloroquinazolin-2-yl)phenol (228 mg, 0.68mmol), triethylamine (129 μL, 0.92 mmol), and CH₂Cl₂ (6 mL) was added(R)-2-hydroxy-4-methyl-1-(piperazin-1-yl)pentan-1-one (185 mg, 0.92mmol) dissolved in CH₂Cl₂ (3 mL). The flask was flushed with N₂ andstirred for 3 hours. The reaction mixture was then transferred into aseparatory funnel with CH₂Cl₂, and the organic phase was washed with H₂O(2×), dried over Na₂SO₄, and concentrated. Purification via silica gelchromatography using 0 to 20% EtOAc and CH₂Cl₂:hexanes (1:1) gave(R)-1-(4-(6-bromo-2-(2-hydroxyphenyl)quinazolin-4-yl)piperazin-1-yl)-2-hydroxy-4-methylpentan-1-one(285 mg, 84%). LC/MS: m/z 500.30 (M+H)⁺ at 3.29 min (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)).

Method B

A solution of 6-bromo-4-chloro-2-(2-hydroxyphenyl)quinazoline (75 mg,0.22 mmol), (R)-2-hydroxy-4-methyl-1-piperazin-1-yl-pentan-1-one (60 mg,0.3 mmol), triethylamine (42 μL, 0.3 mmol), and CH₂Cl₂ (2 mL) wasstirred at room temperature overnight. After diluting with CH₂Cl₂, thereaction mixture was washed with H₂O, dried over Na₂SO₄, andconcentrated. The crude material was purified by silica gelchromatography using 0-10% MeOH/CH₂Cl₂ to give(R)-1-{4-[6-bromo-2-(2-hydroxyphenyl)-quinazolin-4-yl]-piperazin-1-yl}-2-hydroxy-4-methyl-pentan-1-one(40 mg, 36%).

4-[4-((R)-2-Hydroxy-4-methyl-pentanoyl)-piperazin-1-yl]-2-(2-hydroxy-phenyl)-quinazoline-6-carbonitrile

Method A

A mixture of(R)-1-{4-[6-bromo-2-(2-hydroxyphenyl)-quinazolin-4-yl]-piperazin-1-yl}-2-hydroxy-4-methyl-pentan-1-one(20 mg, 0.04 mmol), Zn(CN)₂ (4.7 mg, 0.04 mmol), and Pd(PPh₃)₄ (1.4 mg,1.4 μmol) in DMF (0.5 mL) was heated in a microwave synthesizer at 200°C. for 15 minutes. Purification via preparative HPLC gave4-[4-((R)-2-hydroxy-4-methyl-pentanoyl)-piperazin-1-yl]-2-(2-hydroxy-phenyl)-quinazoline-6-carbonitrileas the TFA salt. LC/MS: m/z 446.3 (M+H)⁺ at 3.17 min (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)).

Method B

(R)-1-(4-(6-Bromo-2-(2-hydroxyphenyl)quinazolin-4-yl)piperazin-1-yl)-2-hydroxy-4-methylpentan-1-one(188 mg, 0.38 mmol), Zn(CN)₂ (44 mg, 0.38 mmol), and Pd(Ph₃)₄ (6.5 mg,0.0112 mmol) were dissolved in DMF (4 mL) and the reaction mixture washeated in a microwave synthesizer at 200° C. for 15 minutes. EtOAc (50mL) was added and the mixture was washed twice with H₂O. The organiclayer was dried over Na₂SO₄, filtered, and concentrated. Purificationvia silica gel chromatography using 0-40% EtOAc in CH₂Cl₂:hexanes (1:1)gave4-[4-((R)-2-hydroxy-4-methyl-pentanoyl)-piperazin-1-yl]-2-(2-hydroxy-phenyl)-quinazoline-6-carbonitrile(127 mg, 75%). LC/MS: m/z 446 (M+H)⁺ at 3.24 min (10%-99% CH₃CN (0.035%TFA)/H₂O (0.05% TFA)). ¹H NMR (400 MHz, DMSO-d6) δ 8.60 (d, J=1.5 Hz,1H), 8.46 (dd, J=8.4, 1.8 Hz, 1H), 8.15 (dd, J=8.7, 1.7 Hz, 1H), 8.00(d, J=8.7 Hz, 1H), 7.45-7.41 (m, 1H), 6.99-6.95 (m, 2H), 4.94 (d, J=7.0Hz, 1H), 4.39-4.36 (m, 1H), 4.14-4.04 (m, 4H), 3.89-3.67 (m, 4H),1.82-1.76 (m, 1H), 1.47-1.37 (m, 2H), 0.93-0.91 (m, 6H) ppm.

4-[4-((R)-2-Hydroxy-4-methyl-pentanoyl)-piperazin-1-yl]-2-(2-hydroxy-phenyl)-quinazoline-6-carbonitrilehydrochloride

4-[4-((R)-2-Hydroxy-4-methyl-pentanoyl)-piperazin-1-yl]-2-(2-hydroxy-phenyl)-quinazoline-6-carbonitrile(137 mg, 0.31 mmol) was dissolved in the minimum amount of CH₂Cl₂. Afterstirring the solution under an N₂ atmosphere for 30 minutes, 1 M HCl inether (0.31 mL, 0.31 mmol) was added dropwise to the solution andstirred for 10 minutes. Ether was added to precipitate the hydrochloridesalt of4-[4-((R)-2-hydroxy-4-methyl-pentanoyl)-piperazin-1-yl]-2-(2-hydroxy-phenyl)-quinazoline-6-carbonitrile,which was filtered and dried to obtain 136 mg of solid (91%). LC/MS: m/z446 (M+H)⁺ at 3.21 min (10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)). ¹HNMR (400 MHz, DMSO-d6) δ 8.62 (s, 1H), 8.43-8.41 (m, 1H), 8.17 (dd,J=8.7, 1.5 Hz, 1H), 8.02 (d, J=8.7 Hz, 1H), 7.47-7.43 (m, 1H), 7.00-6.96(m, 2H), 4.39-4.36 (m, 1H), 4.18-4.00 (m, 4H), 3.91-3.68 (m, 4H),1.85-1.75 (m, 1H), 1.51-1.35 (m, 2H), 0.94-0.91 (m, 6H) ppm; ¹³C NMR(100 MHz, DMSO-d6) δ 172.5, 161.7, 160.6, 135.1, 133.6, 132.4, 129.7,126.9, 118.8, 118.4, 118.2, 117.4, 113.3, 107.3, 66.9, 48.7, 48.1, 43.5,42.8, 41.1, 24.0, 23.4, 21.6.

Example 143(R)-1-(4-(6-Fluoro-2-(2-hydroxyphenyl)quinazolin-4-yl)piperazin-1-yl)-2-hydroxy-4-methylpentan-1-one

(R)-1-(4-(6-Fluoro-2-(2-hydroxyphenyl)quinazolin-4-yl)piperazin-1-yl)-2-hydroxy-4-methylpentan-1-one

Method A

To a solution of 2-(4-chloro-6-fluoroquinazolin-2-yl)phenol (25 mg, 0.09mmol) in DMF (1 mL) was added triethylamine (25 μL, 0.18 mmol) followedby the addition of (R)-2-hydroxy-4-methyl-1-(piperazin-1-yl)pentan-1-oneoxalate (52 mg, 0.18 mmol) at 0° C. The reaction was stirred for 2hours, and purification using reverse phase HPLC (10-99% CH₃CN (0.035%TFA)/H₂O (0.05% TFA)) gave(R)-1-(4-(6-fluoro-2-(2-hydroxyphenyl)quinazolin-4-yl)piperazin-1-yl)-2-hydroxy-4-methylpentan-1-oneas the TFA salt. LC/MS: m/z 439.5 (M+H)⁺ at 2.99 min (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)).

Method B

To a mixture of 2-(4-chloro-6-fluoroquinazolin-2-yl)phenol (200 mg, 0.72mmol) and CH₂Cl₂ (7 mL) was added(R)-2-hydroxy-4-methyl-1-(piperazin-1-yl)pentan-1-one oxalate (275 mg,0.95 mmol). The reaction was complete after two hours. Purification viasilica gel chromatography using 0-10% EtOAc in 50:50 mixture ofCH₂Cl₂:hexanes gave(R)-1-(4-(6-fluoro-2-(2-hydroxyphenyl)quinazolin-4-yl)piperazin-1-yl)-2-hydroxy-4-methylpentan-1-one(289 mg, 91%). LC/MS: m/z 439.30 (M+H)⁺ at 3.00 min (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)). ¹H NMR (400 MHz, DMSO-d6) d 8.46 (m, 1H),8.02 (m, 1H), 7.84 (m, 2H), 7.40 (m, 1H), 6.97 (m, 2H), 4.92 (d, J=7.2Hz, 1H), 4.38 (m, 1H), 3.98 (m, 4H), 3.76 (m, 4H), 1.80 (m, 1H), 1.42(m, 2H), 0.92 (q, J=3.8 Hz, 6H) ppm.

(R)-1-(4-(6-Fluoro-2-(2-hydroxyphenyl)quinazolin-4-yl)piperazin-1-yl)-2-hydroxy-4-methylpentan-1-onehydrochloride

To a solution of(R)-1-(4-(6-fluoro-2-(2-hydroxyphenyl)quinazolin-4-yl)piperazin-1-yl)-2-hydroxy-4-methylpentan-1-one(285 mg, 0.65 mmol) in CH₂Cl₂ (2 mL) under an N₂ atmosphere was addedether (10 mL), followed by the dropwise addition of a 2 M HCl solutionin ether (0.325 mL, 0.65 mmol). A precipitate was formed which wasstirred for 30 min, collected by vacuum filtration, and dried to afford(R)-1-(4-(6-fluoro-2-(2-hydroxyphenyl)quinazolin-4-yl)piperazin-1-yl)-2-hydroxy-4-methylpentan-1-onehydrochloride (284 mg, 92%). LC/MS: m/z 439.30 (M+H)⁺ at 3.00 min(10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)): ¹H NMR (400 MHz, DMSO-d6)d 8.32 (dd, J=8.1, 1.5 Hz, 1H), 8.02 (m, 1H), 7.92 (dd, J=9.7, 2.7 Hz,1H), 7.85 (m, 1H), 7.45 (m, 1H), 7.01 (m, 2H), 4.37 (dd, J=9.2, 4.1 Hz,1H), 4.04 (m, 4H), 3.83 (m, 4H), 1.76 (m, 1H), 1.41 (m, 2H), 0.90 (dd,J=6.6, 3.7 Hz, 6H) ppm.

Example 144(S)-2-Hydroxy-1-(4-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperazin-1-yl)-4-methylpentan-1-one

(S)-2-Hydroxy-1-(4-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperazin-1-yl)-4-methylpentan-1-one

Under an N₂ atmosphere, BOP (137 mg, 0.31 mmol) was added in a singleportion to a stirring solution of2-(7-methyl-4-(piperazin-1-yl)quinazolin-2-yl)phenol (100 mg, 0.31mmol), (S)-2-hydroxy-4-methylpentanoic acid (41 mg, 0.31 mmol), andtriethylamine (43 μL, 0.31 mmol) in DMF (0.5 ml). After stirring themixture for 1 h at room temperature, it was partitioned between H₂O andether. The organic phase was washed with H₂O (3×20 mL), dried overMgSO₄, filtered, and concentrated. Purification via silica gelchromatography using 1:1 ethyl acetate/hexane gave(S)-2-hydroxy-1-(4-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperazin-1-yl)-4-methylpentan-1-oneas a white solid. LC/MS: m/z 435.3 (M+H)⁺ at 2.62 min (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)). ¹H NMR (400 MHz, DMSO-d6) d 8.44 (dd,J=8.2, 1.7 Hz, 1H), 7.99 (d, J=8.5 Hz, 1H), 7.67 (s, 1H), 7.40-7.36 (m,2H), 6.96-6.93 (m, 2H), 4.92 (d, J=7.2 Hz, 1H) 4.41-4.36 (m, 1H),4.06-3.67 (m, 8H), 2.51 (s, 3H), 1.85-1.73 (m, 1H), 1.49-1.35 (m, 2H),0.93-0.91 (m, 6H) ppm.

(S)-2-Hydroxy-1-(4-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperazin-1-yl)-4-methylpentan-1-onehydrochloride

(S)-2-hydroxy-1-(4-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperazin-1-yl)-4-methylpentan-1-one(90 mg, 0.20 mmol) was dissolved in 1 mL CH₂Cl₂ and treated with 1equivalent of 2.0 M HCl in ether (100 μL, 0.20 mmol). The formedprecipitate was filtered and vacuum dried to obtain(S)-2-hydroxy-1-(4-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperazin-1-yl)-4-methylpentan-1-onehydrochloride. LC/MS: m/z 435.5 (M+H)⁺ at 2.62 min (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)). ¹H NMR (400 MHz, DMSO-d6) δ 8.27 (d,J=6.8 Hz, 1H), 8.09 (d, J=8.6 Hz, 1H), 7.78 (s, 1H), 7.50-7.45 (m, 2H),7.09 (d, J=8.2 Hz, 1H), 7.03-6.99 (m, 1H), 4.39-4.35 (m, 1H), 4.16-3.68(m, 8H), 2.54 (s, 3H), 1.84-1.72 (m, 1H), 1.49-1.35 (m, 2H), 0.93 (d,J=2.8 Hz, 6H) ppm.

Example 145(R)-3-Hydroxy-4-(4-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperazin-1-yl)-4-oxobutanoicacid

(R)-3-hydroxy-4-(4-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperazin-1-yl)-4-oxobutanoicacid

(R)-Methyl3-hydroxy-4-(4-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperazin-1-yl)-4-oxobutanoate(88 mg, 0.20 mmol) and LiOH.H₂O (33 mg, 0.78 mmol) were stirred inTHF:H₂O 1:1 at room temperature for 3 h. After acidification with 1 MHCl and extraction with EtOAc, the organic extracts were washed withwater, dried over Na₂SO₄, and concentrated. The crude material was thenpurified via silica gel chromatography using 0-10% MeOH/CH₂Cl₂ to obtain(R)-3-hydroxy-4-(4-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperazin-1-yl)-4-oxobutanoicacid (75 mg, 88%). LC/MS: m/z 437.3 (M+H)⁺ at 2.04 min (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)).

Example 146(R)-1-(4-(2-(2-Chloro-6-hydroxyphenyl)quinazolin-4-yl)piperazin-1-yl)-2-hydroxy-4-methylpentan-1-one

2-Amino-benzamide

Isatoic anhydride (40 g, 245 mmol) was suspended in 650 mL 1 N NH₄OH(2.5 equiv) and stirred at room temperature for 3 days. The precipitatewas filtered and washed with water. The product was then dissolved inTHF, filtered, and concentrated to dryness. The product was dried byazeotropic distillation with toluene and washed with CH₂Cl₂ to yield10.9 g (32.7%) of 2-amino-benzamide.

N-(2-carbamoylphenyl)-2-chloro-6-methoxybenzamide

2-Amino-benzamide (6.9 g, 50.8 mmol) was dissolved in 50 mL of pyridineand cooled to 0° C. 2-Chloro-6-methoxy-benzoyl chloride was addeddropwise to the solution. After complete addition, the reaction was leftto stir at room temperature for three days, which resulted in formationof a brown, cloudy solution. The reaction mixture was then poured into150 mL of ice water. The precipitate was filtered and washed twice withwater, twice with THF and finally twice with CH₂Cl₂ to obtainN-(2-carbamoylphenyl)-2-chloro-6-methoxybenzamide (13.3 g, 43.7 mmol,86%).

2-(2-Chloro-6-methoxy-phenyl)-3H-quinazolin-4-one

N-(2-carbamoylphenyl)-2-chloro-6-methoxybenzamide (13 g, 42.7 mmol) wassuspended in 100 mL of a 2 N NaOH solution and heated to reflux. Afterrefluxing for 3 hours, another 25 mL of a 2 N NaOH solution was added,and the reaction was refluxed for another hour. The mixture was cooledto room temperature and acidified with acetic acid to pH 5. The formedprecipitate was collected by filtration. The product was purified overalumina using EtOAc as an eluent giving 1.7 g (5.9 mmol, 14%) of2-(2-chloro-6-methoxy-phenyl)-3H-quinazolin-4-one.

4-Chloro-2-(2-chloro-6-methoxy-phenyl)-quinazoline

2-(2-Chloro-6-methoxy-phenyl)-3H-quinazolin-4-one (1.7 g, 5.9 mmol) wasdissolved in 25 mL benzene. Then, N,N-dimethylaniline (1.15 mL, 9 mmol)and POCl₃ (1.65 mL, 17.7 mmol) were added. The reaction mixture wasrefluxed for 3 hours during which the yellow suspension changed to adark red color. The mixture was cooled and diluted with 50 mL toluene.The solution was poured onto ice. Saturated aq. NaHCO₃ was added whilestirring and cooling the mixture until the pH remained constant at 7.The layers were separated, and the aqueous layer was extracted with 100mL toluene. The toluene layers were combined and washed with 100 mLsaturated aqueous NaCl solution, 150 mL 0.5 N HCl, 150 mL 5% aq. NaHCO₃and saturated aqueous NaCl solution. The toluene layer was dried overNa₂SO₄, filtered, and concentrated to dryness to yield 1.87 g impureproduct. The product was purified over silica gel with heptane/CH₂Cl₂(2:1) as an eluent to yield4-chloro-2-(2-chloro-6-methoxy-phenyl)-quinazoline (1.22 g, 64%).

3-Chloro-2-(4-chloroquinazolin-2-yl)phenol

To a solution of 4-chloro-2-(2-chloro-6-methoxyphenyl)quinazoline (300mg, 0.98 mmol) in 10 mL CH₂Cl₂ was added dropwise 5 equivalents of a 1 MBBr₃ solution in CH₂Cl₂ at −78° C. The reaction was warmed to roomtemperature and was complete in 30 minutes. The reaction was quenchedwith a saturated aqueous NaHCO₃ solution to pH 7. The aqueous layer wasextracted with CH₂Cl₂, and the combined extracts were dried over Na₂SO₄,filtered, and concentrated to obtain3-chloro-2-(4-chloroquinazolin-2-yl)phenol. LC/MS: m/z 291.3 (M+H)⁺ at3.16 min (10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)).

(R)-1-(4-(2-(2-Chloro-6-hydroxyphenyl)quinazolin-4-yl)piperazin-1-yl)-2-hydroxy-4-methylpentan-1-one

To a solution of 3-chloro-2-(4-chloroquinazolin-2-yl)phenol (42 mg, 0.14mmol) in 2 mL CH₂Cl₂ was added triethylamine (40 μL) followed by theaddition of (R)-2-hydroxy-4-methyl-1-(piperazin-1-yl)pentan-1-one (37.5mg, 0.187 mmol). The reaction was complete after 1 hour. Purificationusing reverse phase HPLC (10-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA))gave(R)-1-(4-(2-(2-chloro-6-hydroxyphenyl)quinazolin-4-yl)piperazin-1-yl)-2-hydroxy-4-methylpentan-1-oneas the TFA salt. LC/MS: m/z 455.5 (M+H)⁺ at 2.45 min (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)).

Example 147(R)-1-(4-(2-(2-Fluoro-6-hydroxyphenyl)-7-methylquinazolin-4-yl)piperazin-1-yl)-2-hydroxy-4-methylpentan-1-one

(R)-1-(4-(2-(2-Fluoro-6-hydroxyphenyl)-7-methylquinazolin-4-yl)piperazin-1-yl)-2-hydroxy-4-methylpentan-1-one

Method A

To a solution of 2-(4-chloro-7-methylquinazolin-2-yl)-3-fluorophenol (50mg, 0.174 mmol) in 1 mL DMF was added triethylamine (35.2 mg, 0.348mmol), followed by the addition of(R)-2-hydroxy-4-methyl-1-(piperazin-1-yl)pentan-1-one (42.1 mg, 0.21mmol). After stirring the reaction for 1 hour, it was filtered, andpurified via preparative reverse phase HPLC (10-99% CH₃CN (0.035%TFA)/H₂O (0.05% TFA)) to obtain(R)-1-(4-(2-(2-fluoro-6-hydroxyphenyl)-7-methylquinazolin-4-yl)piperazin-1-yl)-2-hydroxy-4-methylpentan-1-oneas the TFA salt. LC/MS: m/z 453.3 (M+H)⁺ at 2.40 min (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)).

Method B

2-(4-Chloro-7-methylquinazolin-2-yl)-3-fluorophenol (300 mg, 1.04 mmol)in CH₂Cl₂ (5 mL) was cooled using an ice water batch. To this stirringsolution was added (R)-2-hydroxy-4-methyl-1-(piperazin-1-yl)pentan-1-one(312 mg, 1.56 mmol), followed by triethylamine (210 mg, 291 μL, 2.08mmol). After letting the reaction warn to room temperature, it wasstirred overnight. The mixture was partitioned between water and CH₂Cl₂and separated, and the aqueous layer was extracted with CH₂Cl₂. Thecombined organic layers were dried over Na₂SO₄, filtered, andconcentrated to a viscous yellow oil. Purification via silica gelchromatography using 0-30% EtOAc in CH₂Cl₂/hexanes (2:1) gave(R)-1-(4-(2-(2-fluoro-6-hydroxyphenyl)-7-methylquinazolin-4-yl)piperazin-1-yl)-2-hydroxy-4-methylpentan-1-oneas a bright yellow foam/solid. (413 mg, 88%). LC/MS: m/z 453.1 (M+H)⁺ at2.44 min (10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)). ¹H NMR (400 MHz,DMSO-d6) d 8.01 (d, J=8.5 Hz, 1H), 7.68 (s, 1H), 7.42 (d, J=8.5 Hz, 1H),7.37-7.32 (m, 1H), 6.80 (d, J=8.3 Hz, 1H), 6.76-6.71 (m, 1H), 4.91 (d,J=7.2 Hz, 1H), 4.40-4.35 (m, 1H), 4.02-3.65 (m, 8H), 2.52 (s, 3H),1.82-1.73 (m, 1H), 1.47-1.34 (m, 2H), 0.91 (dd, J=6.5, 4.1 Hz, 6H) ppm.

(R)-1-(4-(2-(2-Fluoro-6-hydroxyphenyl)-7-methylquinazolin-4-yl)piperazin-1-yl)-2-hydroxy-4-methylpentan-1-onehydrochloride

(R)-1-(4-(2-(2-Fluoro-6-hydroxyphenyl)-7-methylquinazolin-4-yl)piperazin-1-yl)-2-hydroxy-4-methylpentan-1-one(406 mg, 0.898 mmol) was dissolved in anhydrous CH₂Cl₂ (3 mL) followedby the addition of Et₂O (6 mL) under an N₂ atmosphere. A 2.0 M HClsolution in Et₂O (0.449 mL, 0.898 mmol) was added over a 2-minuteperiod. The reaction solution changed from a clear yellow solution to aturbid white slurry. After complete addition of the HCl solution, thereaction was allowed to stir for an additional 15 minutes. The productwas collected by vacuum filtration and dried under vacuum to obtain(R)-1-(4-(2-(2-fluoro-6-hydroxyphenyl)-7-methylquinazolin-4-yl)piperazin-1-yl)-2-hydroxy-4-methylpentan-1-onehydrochloride as a white solid (403 mg, 92%). LC/MS: m/z 453.5 (M+H)⁺ at2.44 min (10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)). ¹H NMR (400 MHz,DMSO-d6) d 8.20 (d, J=8.7 Hz, 1H), 7.71 (s, 1H), 7.60-7.60 (m, 1H),7.50-7.44 (m, 1H), 6.99 (d, J=8.4 Hz, 1H), 6.87 (t, J=9.1 Hz, 1H),4.36-4.33 (m, 1H), 4.25-3.67 (m, 8H), 2.57 (s, 3H), 1.83-1.71 (m, 1H),1.49-1.35 (m, 2H), 0.91 (d, J=6.7 Hz, 6H) ppm.

Example 148 (R)-Tetrahydrofuran-3-yl4-(6-fluoro-2-(2-hydroxyphenyl)quinazolin-4-yl)piperazine-1-carboxylate

(R)-Tetrahydrofuran-3-yl chloroformate

A stirred solution of (R)-tetrahydrofuran-3-ol (7.9 g, 90 mmol) inanhydrous CH₂Cl₂ (50 mL) under an N₂ atmosphere was cooled in an icebath, and a 20% solution of phosgene in toluene (134 mL, 270 mmol) wasslowly added. The reaction was allowed to warm to room temperatureovernight, and the solvent was removed under vacuum to afford(R)-tetrahydrofuran-3-yl chloroformate (12.1 g, 85%) as a clear liquid.

(R)-Tetrahydrofuran-3-yl4-(6-fluoro-2-(2-hydroxyphenyl)quinazolin-4-yl)piperazine-1-carboxylate

2-(6-Fluoro-4-(piperazin-1-yl)quinazolin-2-yl)phenol (25 mg, 0.08 mmol),(R) -tetrahydrofuran-3-yl chloroformate (12 mg, 0.08 mmol),triethylamine (22 μL, 0.154 mmol) were stirred in DMF (1 mL) overnight.Purification via reverse phase HPLC (10-99% CH₃CN (0.035% TFA)/H₂O(0.05% TFA)) gave (R)-tetrahydrofuran-3-yl4-(6-fluoro-2-(2-hydroxyphenyl)quinazolin-4-yl)piperazine-1-carboxylateas the TFA salt. LC/MS: m/z 439.5 (M+H)⁺ at 2.80 min (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)).

Example 149 (2R)-(R)-Tetrahydrofuran-3-yl2-(hydroxymethyl)-4-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperazine-1-carboxylate

(2R)-(R)-Tetrahydrofuran-3-yl2-((benzyloxy)methyl)-4-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperazine-1-carboxylate

To a solution of2-(4-((R)-3-((benzyloxy)methyl)piperazin-1-yl)-7-methylquinazolin-2-yl)phenol(75 mg, 0.17 mmol) in DMF (1 mL) was added triethylamine (47 μL)followed by the dropwise addition of (R)-tetrahydrofuran-3-ylchloroformate (25 mg, 0.17 mmol) at 0° C. The reaction was warmed toroom temperature and stirred for 10 minutes. Purification using reversephase HPLC (10-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)) gave(2R)-(R)-tetrahydrofuran-3-yl2-((benzyloxy)methyl)-4-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperazine-1-carboxylateas the TFA salt.

(2R)-(R)-Tetrahydrofuran-3-yl2-(hydroxymethyl)-4-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperazine-1-carboxylate

To a solution of (2R)-(R)-tetrahydrofuran-3-yl2-((benzyloxy)methyl)-4-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperazine-1-carboxylateTFA salt (94 mg, 0.17 mmol) in ethanol was added Pd(OH)₂ (78 mg), andthe reaction was heated at 50° C. under an H₂ atmosphere at ambientpressure. The reaction was filtered, and purification using reversephase HPLC (10-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)) gave(2R)-(R)-tetrahydrofuran-3-yl2-(hydroxymethyl)-4-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperazine-1-carboxylatetrifluoroacetate. LC/MS: m/z 465.5 (M+H)⁺ at 2.23 min (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)).

Example 150(R)-2-Hydroxy-1-(4-(2-(2-hydroxy-6-methylphenyl)-7-methylquinazolin-4-yl)piperazin-1-yl)-4-methylpentan-1-one

2-Methoxy-6-methyl-benzoic acid

Ethyl-2-methoxy-6-methylbenzoate (30.4 g, 0.157 mol) was added to 100 mL3.2 M NaOH (2 equiv) and 150 mL hot EtOH. The mixture was refluxedovernight after which EtOH was removed in vacuo. The aqueous mixture wasacidified with 5 M HCl to pH 3. CH₂Cl₂ (200 mL) was added, and thelayers were separated. The water layer was extracted two times with 200mL CH₂Cl₂, and the organic layers were combined and dried over Na₂SO₄.Filtering the Na₂SO₄ and concentrating the CH₂Cl₂ to dryness yielded21.4 g (0.129 mol, 82.3%) of 2-methoxy-6-methyl-benzoic acid.

2-Methoxy-6-methyl-benzoyl chloride

2-Methoxy-6-methyl-benzoic acid (21.4 g, 0.129 mol) was refluxed for 3hours in 230 mL thionyl chloride. Excess thionyl chloride was removedunder reduced pressure. Co-evaporation of the residue with toluene gave23.8 g of 2-methoxy-6-methyl-benzoyl chloride.

N-(2-Cyano-5-methyl-phenyl)-2-methoxy-6-methyl-benzamide

2-Amino-4-methyl-benzonitrile (15.4 g, 0.117 mol) was dissolved in 100mL pyridine and cooled to 0° C. To this mixture was added dropwise2-methoxy-6-methylbenzoyl chloride (24 g, 0.13 mol, 1.1 equiv). Duringthe addition the temperature did not exceed 2° C. The reaction wasstirred at room temperature for 48 hours. The mixture was poured into400 mL ice water, and the precipitate was collected by filtration andwashed with water. The crude product was dissolved in 600 mL CH₂Cl₂, andthe solution was washed twice with 500 mL of a 1 N HCl solution and oncewith 400 mL of a saturated aq. NaCl solution. The CH₂Cl₂ layer was driedover Na₂SO₄, filtered, and concentrated to dryness to yield 25.44 g(0.09 mol, 77.6%) ofN-(2-cyano-5-methyl-phenyl)-2-methoxy-6-methyl-benzamide.

2-(2-Methoxy-6-methyl-phenyl)-7-methyl-3H-quinazolin-4-one

N-(2-Cyano-5-methyl-phenyl)-2-methoxy-6-methyl-benzamide (25 g, 0.09mol) was suspended in 500 mL EtOH, and 121.3 g of 33% aq. NaOH (1 mol,11 equiv) was added. To this was added a 35% H₂O₂ solution (50 mL, 0.58mol), and the reaction was heated to reflux. Additional H₂O₂ was addeddropwise until the reaction mixture became clear. EtOH was removed underreduced pressure, and the precipitate formed was removed by filtration.The solution was acidified with acetic acid to pH 5, and the precipitateformed was collected by filtration. The precipitate was washed twicewith water and once with diethyl ether. The product was purified overalumina using EtOAc/heptane (1:1) as an eluent. Another purification wasperformed, over silica gel with the same eluent to yield2-(2-methoxy-6-methyl-phenyl)-7-methyl-3H-quinazolin-4-one (1.61 g).

4-Chloro-2-(2-methoxy-6-methyl-phenyl)-7-methyl-quinazoline

2-(2-Methoxy-6-methyl-phenyl)-7-methyl-3H-quinazolin-4-one (1.61 g, 5.74mmol) was suspended in benzene after which was added N,N-dimethylaniline(1.1 mL, 8.62 mmol) and POCl₃ (1.61 mL, 17.27 mmol). The reactionmixture was refluxed for 3 hours during which the color changed fromyellow to dark red. The reaction mixture was cooled to room temperature,diluted with 40 mL toluene and poured onto ice. Saturated aq. NaHCO₃ wascarefully added until the pH remained constant at 7 and no more gasformed. The layers were separated, and the water layer was extractedwith toluene. The organic layers were combined and washed withrespectively 50 mL saturated aq. NaCl, 60 mL 0.5 N HCl, 40 mL 5% NaHCO₃and 50 mL saturated aq. NaCl. The solution was dried over Na₂SO₄ andevaporated to dryness to yield 1.7 g of the impure product. The productwas filtered through silica gel and washed with CH₂Cl₂:heptane (2:1) toyield of 4-chloro-2-(2-methoxy-6-methyl-phenyl)-7-methyl-quinazoline(1.22 g, 71%).

2-(4-Chloro-7-methylquinazolin-2-yl)-3-methylphenol

To a solution of4-chloro-2-(2-methoxy-6-methylphenyl)-7-methylquinazoline (669 mg, 2.24mmol) in 7 mL CH₂Cl₂ was added dropwise 5 equivalents of a 1 M solutionof BBr₃ in CH₂Cl₂ at −78° C. The reaction was warmed to room temperatureand was complete in 30 minutes. The reaction was quenched with asaturated aqueous NaHCO₃ solution until the pH was neutral. The aqueouslayer was extracted with CH₂Cl₂, dried over MgSO₄, filtered, andconcentrated to obtain2-(4-chloro-7-methylquinazolin-2-yl)-3-methylphenol. LC/MS: m/z 285.1(M+H)⁺ at 3.94 min (10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)).

(R)-2-Hydroxy-1-(4-(2-(2-hydroxy-6-methylphenyl)-7-methylquinazolin-4-yl)piperazin-1-yl)-4-methylpentan-1-one

To a solution of 2-(4-chloro-7-methylquinazolin-2-yl)-1-methylphenol (60mg, 2.1 mmol) in 2 mL CH₂Cl₂ was added triethylamine followed by theaddition of (R)-2-hydroxy-4-methyl-1-(piperazin-1-yl)pentan-1-one (54.8mg, 2.73 mmol). The reaction was complete after 1 hour. Purificationusing reverse phase HPLC (10-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA))gave(R)-2-hydroxy-1-(4-(2-(2-hydroxy-6-methylphenyl)-7-methylquinazolin-4-yl)piperazin-1-yl)-4-methylpentan-1-oneas the TFA salt. LC/MS: m/z 449.3 (M+H)⁺ at 2.22 min (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)).

Example 151(R)-2-Hydroxy-1-(4-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperazin-1-yl)pentan-1,4-dione

Methyl 2-((R)-2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)acetate

2-((R)-2,2-Dimethyl-5-oxo-1,3-dioxolan-4-yl)acetic acid (15.8 g, 90.9mmol) in a 3:1 mixture of THF:MeOH (100 mL) was cooled in an ice bath.After adding 2.0 M TMSCHN₂ (50 mL, 100 mmol) the bath was removed, andthe mixture was stirred at room temperature for 3 h. The solvent wasevaporated, and the crude material was purified via silica gelchromatography using 0-50% EtOAc/hexanes to give methyl2-((R)-2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)acetate. ¹H NMR (400 MHz,CDCl₃) d 4.73 (dd, J=6.6, 3.8 Hz, 1H), 3.74 (s, 3H), 2.95 (dd, J=17.0,3.9 Hz, 1H), 2.81 (dd, J=17.0, 6.6 Hz, 1H), 1.63 (s, 3H), 1.57 (s, 3H)ppm.

4-((R)-2-Hydroxy-3-methoxycarbonyl-propionyl)-piperazine-1-carboxylicacid benzyl ester

Methyl 2-((R)-2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)acetate (17.1 g, 90.9mmol) was stirred in a 1:1 mixture of THF:1 M HCl (200 mL) for 1 h atroom temperature. After addition of NaCl to nearly saturate the aqueouslayer, the mixture was extracted with EtOAc, and the extracts were driedover Na₂SO₄ and concentrated. To the resulting oil dissolved in dry DMF(500 mL) was added HOBt (13.5 g, 100 mmol) and EDCI (19.2 g, 100 mmol).After stirring for 5 min, benzyl piperazine-1-carboxylate (19.3 mL, 100mmol) and triethylamine (13.9 mL, 100 mmol) were added to the reactionmixture, which was left stirring at room temperature overnight.Purification via silica gel chromatography using 0-10% MeOH/CH₂Cl₂provided a colorless oil4-((R)-2-hydroxy-3-methoxycarbonyl-propionyl)-piperazine-1-carboxylicacid benzyl ester (6.71 g, 21%). LC/MS: m/z 351.5 (M+H)⁺ at 2.67 min(10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)).

4-((R)-2-Hydroxy-4-oxo-pentanoyl)-piperazine-1-carboxylic acid benzylester

To a solution of4-((R)-2-hydroxy-3-methoxycarbonyl-propionyl)-piperazine-1-carboxylicacid benzyl ester (8.5 g, 24.0 mmol) in THF (240 mL) cooled in a dry iceacetone

bath, was added 1.4 M MeMgBr (61 mL, 85 mmol). The reaction was allowedto slowly warm to room temperature overnight. After quenching themixture with saturated NH₄Cl and extracting with EtOAc, the combinedorganic extracts were washed with water, dried over Na₂SO₄, andconcentrated. Purification via silica gel chromatography using 0-10%MeOH/CH₂Cl₂ gave4-((R)-2-hydroxy-4-oxo-pentanoyl)-piperazine-1-carboxylic acid benzylester as a colorless oil (0.9 g, 11%). ¹H NMR (400 MHz, CDCl₃) δ7.39-7.31 (m, 5H), 5.15 (s, 2H), 4.79-4.74 (m, 1H), 4.00 (d, J=7.8 Hz,1H), 3.75-3.45 (m, 8H), 2.85 (dd, J=16.6, 7.3 Hz, 1H), 2.63 (dd, J=16.6,3.4 Hz, 1H), 2.26 (s, 3H) ppm; LC/MS: m/z 335.1 (M+H)⁺ at 2.17 min(10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)).

(R)-2-hydroxy-1-(4-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperazin-1-yl)pentan-1,4-dione

A mixture of 4-((R)-2-hydroxy-4-oxo-pentanoyl)-piperazine-1-carboxylicacid benzyl ester (0.13 g, 0.39 mmol) and MeOH (4 mL) was stirred with10 mg of Pd/C (10% wt Pd on carbon) under H₂ atmosphere at ambientpressure overnight. After filtration and evaporation of the solvent, theresidue was taken up in CH₂Cl₂, and2-(4-chloro-7-methylquinazolin-2-yl)phenol (0.11 g, 0.39 mmol) andtriethylamine (0.11 mL, 0.78 mmol) were added. The reaction mixture wasstirred at room temperature overnight, washed with water, dried overNa₂SO₄, and concentrated. Purification via silica gel chromatographyusing 0-10% MeOH/CH₂Cl₂ provided(R)-2-hydroxy-1-(4-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperazin-1-yl)pentan-1,4-dioneas a yellow solid (91 mg, 54%). LC/MS: m/z 435.5 (M+H)⁺ at 2.13 min(10%-99% CH₃CN (0.035% TFA)/H₂O (0.05%TFA))yl)piperazin-1-yl)pentan-1,4-dione as a yellow solid (91 mg, 54%).LC/MS: m/z 435.5 (M+H)⁺ at 2.13 min (10%-99% CH₃CN (0.035% TFA)/H₂O(0.05% TFA)).

Example 152 (Pyridin-4-yl)methyl4-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperazine-1-carboxylate

(Pyridin-4-yl)methyl4-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperazine-1-carboxylate

A solution of 2-(7-methyl-4-(piperazin-1-yl)quinazolin-2-yl)phenol (50mg, 0.16 mmol), (pyridin-4-yl)methyl 1H-imidazole-1-carboxylate (67 mg,0.32 mmol), and triethylamine (44.6 μL, 0.32 mmol) in DMSO (500 μL) washeated in a microwave synthesizer at 200° C. for 10 minutes.Purification using reverse phase HPLC (10-99% CH₃CN (0.035% TFA)/H₂O(0.05% TFA)) gave (pyridin-4-yl)methyl4-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperazine-1-carboxylateas the TFA salt. LC/MS: m/z 456.5 (M+H)⁺ at 2.02 min (10%99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)).

Example 1532-Hydroxy-1-(4-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperazin-1-yl)-4-(methylthio)butan-1-one

1-(4-(2-(2-Hydroxyphenyl)-7-methylquinazolin-4-yl)piperazin-1-yl)-4-(methylthio)butane-1,2-dione

A mixture of 2-(7-methyl-4-(piperazin-1-yl)quinazolin-2-yl)phenol (200mg, 0.63 mmol), sodium 4-methylsulfanyl-2-oxo-butyrate (160 mg, 0.94mmol), BOP (414 mg, 0.94 mmol), and triethylamine (348 μL, 2.5 mmol) in2.1 mL of CH₂Cl₂ was stirred at room temperature for 1 h. After addingsaturated NaHCO₃ solution, the mixture was extracted with CH₂Cl₂. Theorganic extracts were dried over Na₂SO₄ and concentrated to give1-(4-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperazin-1-yl)-4-(methylthio)butane-1,2-dione.LC/MS: m/z 451.2 (M+H)⁺ at 3.10 min (10%-99% CH₃CN (0.035% TFA)/H₂O(0.05% TFA)).

2-Hydroxy-1-(4-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperazin-1-yl)-4-(methylthio)butan-1-one

NaBH₄ (34 mg, 0.88 mmol) was added to1-(4-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperazin-1-yl)-4-(methylthio)butane-1,2-dione(200 mg, 0.44 mmol) in 1.5 mL of MeOH, and the reaction mixture wasstirred at 0° C. for 20 minutes The reaction mixture was allowed to warmto room temperature, saturated NaHCO₃ was added, and the aqueous layerwas extracted with CH₂Cl₂. The organic layer was dried over Na₂SO₄ andconcentrated. Purification using preparative reverse phase HPLC with10-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA) gave2-hydroxy-1-(4-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperazin-1-yl)-4-(methylthio)butan-1-oneas the TFA salt. (LC/MS: m/z 453.4 (M+H)⁺ at 2.73 min (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)).

Example 154(R)-3-Hydroxy-4-(4-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperazin-1-yl)-4-oxobutanamide

(R)-3-Hydroxy-4-(4-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperazin-1-yl)-4-oxobutanamide

(R)-3-Hydroxy-4-{4-[2-(2-hydroxy-phenyl)-7-methyl-quinazolin-4-yl]-piperazin-1-yl}-4-oxo-butyricacid (17 mg, 0.039 mmol) and HATU (16 mg, 0.043 mmol) were stirred inDMF (0.5 mL). After adding 0.5 M NH₃ in dioxane (0.38 mL, 0.19 mmol),the reaction mixture was stirred at room temperature for 5 h.Purification via preparative reverse phase HPLC (10-99% CH₃CN (0.035%TFA)/H₂O (0.05% TFA)) gave(R)-3-hydroxy-4-(4-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperazin-1-yl)-4-oxobutanamideas the TFA salt. LC/MS: m/z 436.3 (M+H)⁺ at 1.94 min (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)).

Example 155(R)-2-Hydroxy-1-((S)-4-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)-3-isopropylpiperazin-1-yl)-4-methylpentan-1-one

To a solution of 2-(4-chloro-7-methylquinazolin-2-yl)phenol (200 mg,0.74 mmol) in 10 mL DMF was added (S)-1-benzyl-3-isopropylpiperazinefollowed by the addition of triethylamine (206 μL). The reaction washeated at 85° C. for two hours. The reaction was quenched with waterafter cooling it to room temperature. The aqueous layer was extractedtwice with CH₂Cl₂, and the combined extracts were dried over MgSO₄,filtered, and concentrated. The reaction was purified via silica gelchromatography using 1:1 hexanes:CH₂Cl₂ solvent system to yield2-(4-((S)-4-benzyl-2-isopropylpiperazin-1-yl)-7-methylquinazolin-2-yl)phenol(230 mg, 64%). LC/MS: m/z 453.5 (M+H)⁺ at 2.61 min (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)).

2-(4-((S)-2-Isopropylpiperazin-1-yl)-7-methylquinazolin-2-yl)phenol

20 mg of Pd/C was added to a round-bottom flask, and the flask wasflushed with nitrogen followed by evacuation of the atmosphere undervacuum. To the flask was then added a solution of2-(4-((S)-4-benzyl-2-isopropylpiperazin-1-yl)-7-methylquinazolin-2-yl)phenol(200 mg, 0.44 mmol) in methanol, followed by the addition of ammoniumformate (32 mg, 0.88 mmol). The reaction was refluxed overnight. Thereaction was filtered through a bed of Celite to remove the catalyst.The solvent was evaporated to yield2-(4-((S)-2-isopropylpiperazin-1-yl)-7-methylquinazolin-2-yl)phenol (126mg). LC/MS: m/z 363.5 (M+H)⁺ at 2.13 min (10%-99% CH₃CN (0.035% TFA)/H₂O(0.05% TFA)).

(R)-2-Hydroxy-1-((S)-4-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)-3-isopropylpiperazin-1-yl)-4-methylpentan-1-one

To a solution of2-(4-((S)-2-isopropylpiperazin-1-yl)-7-methylquinazolin-2-yl)phenol (70mg, 0.19 mmol) in DMF (0.5 mL) was added (R)-2-hydroxy-4-methylpentanoicacid (32.6 mg, 0.247 mmol). It was followed by the addition oftriethylamine (52 μL) and a solution of HATU (94 mg) in 0.5 mL DMF atroom temperature. The reaction was complete in an hour. Purificationusing reverse phase HPLC (10-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA))gave(R)-2-hydroxy-1-((S)-4-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)-3-isopropylpiperazin-1-yl)-4-methylpentan-1-oneas the TFA salt. LC/MS: m/z 477.5 (M+H)⁺ at 2.96 min (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)).

Example 156 (Pyridin-3-yl)methyl4-(2-(2-fluoro-6-hydroxyphenyl)-7-methylquinazolin-4-yl)piperazine-1-carboxylate

(Pyridin-3-yl)methyl4-(2-(2-fluoro-6-hydroxyphenyl)-7-methylquinazolin-4-yl)piperazine-1-carboxylate

3-Fluoro-2-(7-methyl-4-(piperazin-1-yl)quinazolin-2-yl)phenol (50 mg,0.15 mmol), (pyridin-3-yl)methyl 1H-imidazole-1-carboxylate (53 mg, 0.26mmol), triethylamine (30.4 mg, 0.3 mmol) and DMSO (1 mL) were stirredfor 18 hours at room temperature. The reaction was purified bypreparative reverse phase HPLC to give (pyridin-3-yl)methyl4-(2-(2-fluoro-6-hydroxyphenyl)-7-methylquinazolin-4-yl)piperazine-1-carboxylateas the TFA salt. LC/MS: m/z 474.30 (M+H)⁺ at 1.19 min (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)).

Example 1573-Hydroxymethyl-4-[2-(2-hydroxy-phenyl)-7-methyl-quinazolin-4-yl]-piperazine-1-carboxylicacid benzyl ester

3-Hydroxymethyl-4-[2-(2-hydroxy-phenyl)-7-methyl-quinazolin-4-yl]-piperazine-1-carboxylicacid benzyl ester

To 2-(4-chloro-7-methyl-quinazolin-2-yl)-phenol (245 mg, 0.91 mmol) in3.0 mL of CH₂Cl₂ was added sequentially3-hydroxymethyl-piperazine-1-carboxylic acid benzyl ester (336.3 mg,1.34 mmol) and triethylamine (190 mL, 1.37 mmol), and the reactionmixture was heated at 40° C. for 6 h. The reaction mixture was cooledand extracted with water (2×10 mL) and the organic layer was separatedand dried over Na₂SO₄. The solvent was removed under reduced pressure togive an oil. The residue was purified by normal phase LC (20-85%EtOAc-hexanes) to give3-hydroxymethyl-4-[2-(2-hydroxy-phenyl)-7-methyl-quinazolin-4-yl]-piperazine-1-carboxylicacid benzyl ester (216 mg, 64% yield). LC/MS: m/z 485.4 (M+H)⁺ at 3.02min (10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)).

Benzyl3-(hydroxymethyl)-4-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperazine-1-carboxylatehydrochloride

A 2.0 M HCl solution in Et₂O (212 μL, 0.42 mmol) was slowly added atroom temperature to a stirring solution of3-hydroxymethyl-4-[2-(2-hydroxy-phenyl)-7-methyl-quinazolin-4-yl]-piperazine-1-carboxylicacid benzyl ester (206 mg, 0.42 mmol) in 500 μL of CH₂Cl₂. The reactionwas stirred for 1 hour. Solvents were removed under reduced pressure,and the residue was triturated with Et₂O and filtered to give benzyl3-(hydroxymethyl)-4-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperazine-1-carboxylatehydrochloride. LC/MS: m/z 485.5 (M+H)+ at 3.07 min (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA))

Example 1582-Hydroxy-1-(4-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperazin-1-yl)but-3-yn-1-one

2-Hydroxy-1-(4-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperazin-1-yl)but-3-yn-1-one

To a mixture of 2-(7-methyl-4-(piperazin-1-yl)quinazolin-2-yl)phenol (75mg, 0.23 mmol) in 0.78 ml CH₂Cl₂ were added successively2-hydroxybut-3-ynoic acid (30 mg, 0.30 mmol), BOP (134 mg, 0.30 mmol),and triethylamine (36 mg, 49 μL, 0.35 mmol). The mixture was stirred at0° C. for 30 minutes. Purification via silica gel chromatography using0-100% ethyl acetate/hexanes gave2-hydroxy-1-(4-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperazin-1-yl)but-3-yn-1-one.(LC/MS: m/z 403.5 (M+H)⁺ at 2.34 min (10%-99% CH₃CN (0.035% TFA)/H₂O(0.05% TFA)).

Example 1592-Hydroxy-1-(4-(2-(2-hydroxyphenyl)quinazolin-4-yl)piperazin-1-yl)hexan-1-one

2-Hydroxy-1-(4-(2-(2-hydroxyphenyl)quinazolin-4-yl)piperazin-1-yl)hexan-1-one

A solution of 2-(4-(piperazin-1-yl)quinazolin-2-yl)phenol (70 mg, 0.23mmol) in DMF (0.5 mL) was added to 2-hydroxyhexanoic acid (39.3 mg,0.297 mmol). Triethylamine (63 μL) was added at room temperature, then asolution of HATU (113 mg) in 0.5 mL DMF. The reaction was stirredovernight. Purification using reverse phase HPLC (10-99% CH₃CN (0.035%TFA)/H₂O (0.05% TFA)) gave2-hydroxy-1-(4-(2-(2-hydroxyphenyl)quinazolin-4-yl)piperazin-1-yl)-2-methylbutan-1-one.LC/MS: m/z 421.3 (M+H)⁺ at 2.60 min (10%-99% CH₃CN (0:035% TFA)/H₂O(0.05% TFA)).

Example 160 (Tetrahydro-2H-pyran-2-yl)methyl4-(6-fluoro-2-(2-hydroxyphenyl)quinazolin-4-yl)piperazine-1-carboxylate

(Tetrahydro-2H-pyran-2-yl)methyl 1H-imidazole-1-carboxylate

A solution of (tetrahydro-2H-pyran-2-yl)methanol (1 g, 8.60 mmol) anddi(1H-imidazol-1-yl)methanone (2.8 g, 17.2 mmol) in 17 mL CH₂Cl₂ washeated overnight at 50° C. The reaction was quenched with water,extracted with CH₂Cl₂, dried over MgSO₄, filtered, and concentrated.

(Tetrahydro-2H-pyran-2-yl)methyl 4-(6-fluoro-2-(2-hydroxyphenyl)quinazolin-4-yl)piperazine-1-carboxylate

2-(6-Fluoro-4-(piperazin-1-yl)quinazolin-2-yl)phenol (25 mg, 0.077mmol), (tetrahydro-2H-pyran-2-yl)methyl 1H-imidazole-1-carboxylate (48.5mg, 0.23 mmol), triethylamine (22 μL, 0.154 mmol) were stirred in DMF (1mL) overnight. Purification via reverse phase HPLC (10-99% CH₃CN (0.035%TFA)/H₂O (0.05% TFA)) gave (tetrahydro-2H-pyran-2-yl)methyl4-(6-fluoro-2-(2-hydroxyphenyl)quinazolin-4-yl)piperazine-1-carboxylateas the TFA salt. LC/MS: m/z 467.3 (M+H)⁺ at 3.13 min (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)).

Example 162 (Tetrahydrofuran-3-yl)methyl4-(2-(2-fluoro-6-hydroxyphenyl)-7-methylquinazolin-4-yl)piperazine-1-carboxylate

4-Benzyl-piperazine-1-carboxylic acid tetrahydro-furan-3-ylmethyl ester

To a cooled (0° C.) solution of triphosgene (5.0 g, 17 mmol) in 50 mldichloromethane under a nitrogen atmosphere was added dropwise asolution of tetrahydro-3-furanmethanol (5.4 g, 53 mmol) in 10 mldichloromethane. Pyridine (4.3 ml, 53 mmol) was added dropwise, and thesolution was warmed to room temperature. After 2 hours at roomtemperature a mixture of triethylamine (7.5 ml, 52 mmol) andN-benzylpiperazine (9.5 ml, 54 mmol) was added dropwise with cooling.The resulting mixture was refluxed for 1 hour. The solution was stirredat room temperature overnight under an nitrogen atmosphere. The mixturewas washed with aqueous sodium bicarbonate solution (5%, 2×50 ml), andwith a solution of saturated aqueous NaCl (50 ml). The organic layer wasdried over sodium sulfate, filtered, and evaporated to dryness. Theresidue was co-evaporated three times with toluene (50 ml) to yield4-benzyl-piperazine-1-carboxylic acid tetrahydro-furan-3-ylmethyl ester(13.0 g, 81%) as a brownish oil.

Piperazine-1-carboxylic acid tetrahydro-furan-3-ylmethyl ester

4-Benzyl-piperazine-1-carboxylic acid tetrahydro-furan-3-ylmethyl ester(11.0 g) was dissolved in 100 ml ethanol. Palladium on carbon (10% Pd/C,0.5 g) was added, and a hydrogen atmosphere was applied overnight atroom temperature. The solution was filtered through Celite to remove thecatalyst, and the Celite cake was rinsed with 50 ml ethanol. Thecombined filtrates were evaporated to dryness to yieldpiperazine-1-carboxylic acid tetrahydro-furan-3-ylmethyl ester (8.0 g)as a colorless oil.

(Tetrahydrofuran-3-yl)methyl4-(2-(2-fluoro-6-hydroxyphenyl)-7-methylquinazolin-4-yl)piperazine-1-carboxylate

2-(4-Chloro-7-methylquinazolin-2-yl)-3-fluorophenol (50 mg, 0.174 mmol)was dissolved in 1 mL DMF, followed by the addition of triethylamine(35.2 mg, 0.348 mmol). (Tetrahydrofuran-3-yl)methylpiperazine-1-carboxylate (45 mg, 0.21 mmol) was then added. After 1 hourat room temperature, the reaction was complete. It was filtered andpurified by reverse phase preparative HPLC to give(tetrahydrofuran-3-yl)methyl4-(2-(2-fluoro-6-hydroxyphenyl)-7-methylquinazolin-4-yl)piperazine-1-carboxylateas the TFA salt. LC/MS: m/z 467.3 (M+H)⁺ at 2.33 min (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)).

Example 163 (S)-Tetrahydrofuran-3-yl4-(2-(2-fluoro-6-hydroxyphenyl)-7-methylquinazolin-4-yl)piperazine-1-carboxylate

(S)-Tetrahydrofuran-3-yl4-(2-(2-fluoro-6-hydroxyphenyl)-7-methylquinazolin-4-yl)piperazine-1-carboxylate

3-Fluoro-2-(7-methyl-4-(piperazin-1-yl)quinazolin-2-yl)phenol (70 mg,0.21 mmol) was dissolved in 1 mL anhydrous DMF under an N₂ atmosphereand cooled to 0° C. (S)-Tetrahydrofuran-3-yl chloroformate (34.3 mg,0.228 mmol) was dissolved in 150 μL anhydrous DMF and added dropwise tothe reaction, followed by triethylamine (42 mg, 0.41 mmol). After 1 hourthe reaction was complete, and it was filtered and purified by reversephase HPLC to give (S)-tetrahydrofuran-3-yl4-(2-(2-fluoro-6-hydroxyphenyl)-7-methylquinazolin-4-yl)piperazine-1-carboxylateas the TFA salt. LC/MS: m/z 453.3 (M+H)⁺ at 2.25 min (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)).

Example 164(R)-2,4-Dihydroxy-1-(4-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperazin-1-yl)-4-methylpentan-1-one

(R)-Benzyl-4-(2-hydroxy-4-methoxy-4-oxobutanoyl)piperazine-1-carboxylate

To a solution of4-((R)-2-hydroxy-3-methoxycarbonyl-propionyl)-piperazine-1-carboxylicacid benzyl ester (5.26 g, 15.0 mmol) in THF (150 mL) cooled in a dryice acetone bath was added 1.4 M MeMgBr (32 mL, 45 mmol). The reactionwas allowed to slowly warm to room temperature overnight. Afterquenching the mixture with saturated NH₄Cl and extracting with EtOAc,the combined organic extracts were washed with water, dried over Na₂SO₄,and concentrated. Purification via silica gel chromatography using 0-10%MeOH/CH₂Cl₂ gave(R)-benzyl-4-(2-hydroxy-4-methoxy-4-oxobutanoyl)piperazine-1-carboxylateas a colorless oil (0.79 g, 15%). ¹H NMR (400 MHz, CDCl₃) δ 7.40-7.31(m, 5H), 5.15 (s, 2H), 4.71-4.68 (m, 1H), 4.05 (d, J=6.8 Hz, 1H),3.80-3.73 (m, 1H), 3.62-3.42 (m, 6H), 3.31-3.23 (m, 1H), 1.72-1.61 (m,2H), 1.35 (s, 3H), 1.30 (s, 3H) ppm; LC/MS: m/z 351.3 (M+H)⁺ at 2.22 min(10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)).

(R)-2,4-Dihydroxy-1-(4-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperazin-1-yl)-4-methylpentan-1-one

A mixture of(R)-Benzyl-4-(2-hydroxy-4-methoxy-4-oxobutanoyl)piperazine-1-carboxylate(0.79 g, 2.20 mmol) and MeOH (25 mL) was stirred with 40 mg of Pd/C (10%wt Pd on carbon) under H₂ atmosphere at ambient pressure overnight.After filtration and evaporation of the solvent, the residue was takenup in CH₂Cl₂, and 2-(4-chloro-7-methylquinazolin-2-yl)phenol (0.61 g,2.20 mmol) and triethylamine (0.63 mL, 4.50 mmol) were added. Thereaction mixture was stirred at room temperature overnight and thendiluted with CH₂Cl₂, washed with water, dried over Na₂SO₄, andconcentrated. Purification via silica gel chromatography using 0-10%MeOH/CH₂Cl₂ gave(R)-2,6-dihydroxy-1-(4-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperazin-1-yl)4-methylpentan-1-one as a yellow solid (372 mg, 37%). ¹H NMR (400 MHz,CDCl₃) δ 8.45 (dd, J 8.5 Hz, 1H), 7.67 (s, 1H), 7.40-7.36 (m, 1H), 7.29(dd, J=8.5, 1.4 Hz, 1H), 7.03 (d, J=8.2 Hz, 1H), 6.96-6.92 (m, 1H),4.81-4.76 (m, 1H), 4.09 (d, J=6.8 Hz, 1H), 4.03-3.77 (m, 6H), 3.75-3.67(m, 2H), 3.28 (s, 1H), 2.55 (s, 3H), 1.78-1.69 (m, 2H), 1.40 (s, 3H),1.33 (s, 3H) ppm; ¹³C NMR (100 MHz, CDCl₃) δ 173.1, 164.0, 161.3, 160.5,150.1, 144.5, 132.7, 129.2, 127.7, 126.8, 124.4, 119.3, 118.5, 117.7,112.7, 70.6, 66.4, 49.9, 49.0, 46.1, 44.5, 42.4, 30.6, 29.2, 21.9;LC/MS: m/z 451.1 (M+H)⁺ at 2.12 min (10%-99% CH₃CN (0.035% TFA)/H₂O(0.05% TFA)).

Example 1652-Hydroxy-1-(4-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperazin-1-yl)-2-methylbutan-1-one

2-Hydroxy-1-(4-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperazin-1-yl)-2-methylbutan-1-one

A solution of 2-(7-methyl-4-(piperazin-1-yl)quinazolin-2-yl)phenol (70mg, 0.22 mmol) in DMF (0.5 mL) was added to 2-hydroxy-2-methylbutanoicacid (33.6 mg, 0.284 mmol). Triethylamine (61 μL) was added, followed bya solution of HATU (108 mg) in 0.5 mL DMF at room temperature. Thereaction was stirred overnight. Purification using reverse phase HPLC(10-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)) gave2-hydroxy-1-(4-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperazin-1-yl)-2-methylbutan-1-oneas the TFA salt. LC/MS: m/z 421.3 (M+H)⁺ at 2.40 min (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)).

Example 166(S)-2-Hydroxy-1-(4-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperazin-1-yl)-3,3-dimethylbutan-1-one

(S)-2-Hydroxy-1-(4-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperazin-1-yl)-3,3-dimethylbutan-1-one

2-(7-Methyl-4-(piperazin-1-yl)quinazolin-2-yl)phenol hydrochloride (30mg, 0.09 mmol), (S)-2-hydroxy-3,3-dimethylbutanoic acid (16 mg, 0.12mmol), triethylamine (37.5 μL, 0.27 mmol), and HATU (45.6 mg, 0.12 mmol)were stirred in DMF (1 mL) overnight. Purification via reverse phaseHPLC (10-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)) gave(S)-2-hydroxy-1-(4-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperazin-1-yl)-3,3-dimethylbutan-1-oneas the TFA salt. LC/MS: m/z 434.53 (M+H)⁺ at 2.61 min (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)).

Example 1671-(4-(2-(2-Fluoro-6-hydroxyphenyl)-7-methylquinazolin-4-yl)piperazin-1-yl)-2-(4-fluorophenyl)-2-hydroxyethanone

1-(4-(2-(2-Fluoro-6-hydroxyphenyl)-7-methylquinazolin-4-yl)piperazin-1-yl)-2-(4-fluorophenyl)-2-hydroxyethanone

3-Fluoro-2-(7-methyl-4-(piperazin-1-yl)quinazolin-2-yl)phenol (30 mg,0.09 mmol), 2-(4-fluorophenyl)-2-hydroxyacetic acid (19.62 mg, 0.12mmol), triethylamine (25 μL, 0.18 mmol) and HATU (45.6 mg, 0.12 mmol)were stirred in DMF (1 mL) overnight. Purification via reverse phaseHPLC (10-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)) gave1-(4-(2-(2-fluoro-6-hydroxyphenyl)-7-methylquinazolin-4-yl)piperazin-1-yl)-2-(4-fluorophenyl)-2-hydroxyethanoneas the TFA salt. LC/MS: m/z 491.3 (M+H)⁺ at 2.46 min (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)).

Example 168(R)-2-Hydroxy-1-(4-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperazin-1-yl)-4-methylpentan-1-one

(R)-2-Hydroxy-1-(4-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperazin-1-yl)-4-methylpentan-1-one

Under an N₂ atmosphere, BOP (138 mg, 0.31 mmol) was added in a singleportion to a stirring solution of2-(7-methyl-4-(piperazin-1-yl)quinazolin-2-yl)phenol (100 mg, 0.31mmol), (R)-2-hydroxy-4-methylpentanoic acid (41 mg, 0.31 mmol), andtriethylamine (43 μL, 0.31 mmol) in DMF (0.5 ml). After stirring themixture for 1 h at room temperature, it was partitioned between H₂O andether. The organic phase was washed with H₂O (3×20 mL), dried overMgSO₄, filtered, and concentrated. Purification via silica gelchromatography using 20% EtOAc and 80% CH₂Cl₂ gave(R)-2-hydroxy-1-(4-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperazin-1-yl)-4-methylpentan-1-oneas a light yellow solid (89 mg, 60%). LC/MS: m/z 435.1 (M+H)⁺ at 2.93min (10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)). ¹H NMR (400 MHz,CDCl₃) δ 8.46 (dd, J=7.9, 1.7 Hz, 1H), 7.76 (d, J=8.5 Hz, 1H), 7.66 (s,1H), 7.41-7.37 (m, 1H), 7.30 (dd, J=8.5, 1.5 Hz, 1H), 7.06-7.04 (m, 1H),6.98-6.94 (m, 1H), 4.51-4.45 (m, 1H), 4.04-3.80 (m, 6H), 3.72-3.62 (m,3H), 2.56 (s, 3H), 2.12-1.99 (m, 1H), 1.57-1.49 (m, 1H), 1.38-1.32 (m,1H), 1.05 (d, J=6.6 Hz, 3H), 1.00 (d, J=6.7 Hz, 3H) ppm.

(R)-2-Hydroxy-1-(4-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperazin-1-yl)-4-methylpentan-1-onehydrochloride

(R)-2-hydroxy-1-(4-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperazin-1-yl)-4-methylpentan-1-one(90 mg, 0.20 mmol) was dissolved in 1 mL CH₂Cl₂ and treated with 1equivalent of 2.0 M HCl in ether (100 μL, 0.20 mmol). The formedprecipitate was filtered and vacuum dried to obtain(R)-2-hydroxy-1-(4-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperazin-1-yl)-4-methylpentan-1-onehydrochloride. LC/MS: m/z 435.1 (M+H)⁺ at 2.84 min (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)). ¹H NMR (400 MHz, CD 30D) δ 8.39-8.37 (m,1H), 8.18 (d, J=8.6 Hz, 1H), 7.78 (s, 1H), 7.61-7.55 (m, 2H), 7.15-7.11(m, 2H), 4.57 (dd, J=9.5, 3.5 Hz, 1H), 4.49-4.32 (m, 4H), 4.07-3.79 (m,4H), 2.62 (s, 3H), 1.97-1.87 (m, 1H), 1.65-1.58 (m, 1H), 1.53-1.47 (m,1H), 1.03-1.00 (m, 6H) ppm.

(R)-2-Hydroxy-1-(4-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperazin-1-yl)-4-methylpentan-1-onesulfate

To a stirring yellow solution of(R)-2-hydroxy-1-(4-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperazin-1-yl)-4-methylpentan-1-one(200 mg, 0.46 mmol) and THF (0.9 mL) under an N₂ atmosphere was added asolution of concentrated H₂SO₄ solution (95.9%) (26 μL, 0.46 mmol) andCH₃CN (0.75 mL) in a single portion. A white precipitate formed slowlyover a period of 1 h. The solid was filtered and vacuum dried to obtain(R)-2-hydroxy-1-(4-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperazin-1-yl)-4-methylpentan-1-onesulfate as a white solid (229 mg, 94%). LC/MS: m/z 435.3 (M+H)⁺ at 2.81min (10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)). ¹H NMR (400 MHz,DMSO-d6) δ 8.20 (dd, J=7.9, 1.5 Hz, 1H), 8.12 (d, J=8.6 Hz, 1H), 7.77(s, 1H), 7.53-7.49 (m, 2H), 7.10-7.03 (m, 2H), 4.39-4.35 (m, 1H),4.30-4.04 (m, 4H), 3.93-3.69 (m, 4H), 2.55 (s, 3H), 1.86-1.73 (m, 1H),1.52-1.33 (m, 2H), 0.93-0.91 (m, 6H) ppm.

Example 169 (R)-[Methyl-(2-methylamino-acetyl)-amino]-acetic acid1-{4-[2-(2-hydroxy-phenyl)-7-methyl-quinazolin-4-yl]-piperazine-1-carbonyl}-3-methyl-butylester

{[2-(tert-Butoxycarbonyl-methyl-amino)-acetyl]-methyl-amino}-acetic acid

To (tert-butoxycarbonyl-methyl-amino)-acetic acid (2.73 g, 14.4 mmol) in70 mL of THF was added sequentially diisopropyl ethylamine (7.5 mL, 14.4mmol) and HBTU (5.47 g, 14.4 mmol), and the reaction mixture was stirredat room temperature for one hour. To this reaction mixture was addedmethylamino-acetic acid ethyl ester (2.22 g, 14.4 mmol) in one portion,and the reaction mixture was heated at 65° C. for 12 h. The reactionmixture was cooled, diluted with a solution of saturated NaHCO₃, andextracted with EtOAc. The organic layer was separated and dried overNa₂SO₄, and the solvent was removed under reduced pressure to give{[2-(tert-butoxycarbonyl-methyl-amino)-acetyl]-methyl-amino}-acetic acidethyl ester.

The ester was taken up in 49 mL of methanol, and to this was added a 1 MNaOH solution (25.1 mL, 25 mmol). The reaction mixture was heated at 65°C. for 3 h. The reaction mixture was cooled, and methanol was removedunder reduced pressure. The residue was diluted with 50 mL of water andacidified with glacial acetic acid until the pH was 5. This solution wasextracted with EtOAc (50 mL), and the organic layer was separated anddried over Na₂SO₄, and the solvent was removed under reduced pressure togive {[2-(tert-Butoxycarbonyl-methyl-amino)-acetyl]-methyl-amino}-aceticacid as an oil.

4-(2(R)-Hydroxy-4-methyl-pentanoyl)-piperazine-1-carboxylic acid benzylester

To (R)-2-hydroxy-4-methyl-pentanoic acid (1.71 g, 12.9 mmol) in 48 mL ofDMF was added sequentially triethylamine (4.9 mL, 35 mmol), HOBt (1.75g, 12.9 mmol), EDCI.HCl (2.48 g, 12.9 mmol) and piperazine-1-carboxylicacid benzyl ester (2.59 g, 11.8 mmol) at room temperature. The reactionmixture was stirred for 4 h and then diluted with EtOAc (50 mL) andextracted with 50 mL of water. The organic layer was separated and driedover Na₂SO₄, and the solvent was removed under reduced pressure to givean oil. The residue was subjected to purification by normal phase LCusing 40-85% EtOAc-hexanes to give (1.92 g, 49% yield) of4-(2(R)-hydroxy-4-methyl-pentanoyl)-piperazine-1-carboxylic acid benzylester the desired product. LC/MS: m/z 335.4 (M+H)⁺ at 2.96 min (10%-99%CH₃CN (0.035% TFA)/H₂O (0.05% TFA)).

4-[2-(2-{[2-(tert-Butoxycarbonyl-methyl-amino)-acetyl]-methyl-amino}-acetoxy)-4-methyl-pentanoyl]-piperazine-1-carboxylicacid benzyl ester

To {[2-(tert-butoxycarbonyl-methyl-amino)-acetyl]-methyl-amino}-aceticacid (427 mg, 1.57 mmol) in 2 mL of THF was added sequentially HBTU (624mg, 1.2 mmol), diisopropyl ethylamine (860 μL, 4.71 mmol) at roomtemperature. After 5 min,4-(2-hydroxy-4-methyl-pentanoyl)-piperazine-1-carboxylic acid benzylester (403 mg 1.2 mmol) in 2 mL of THF was added to the reactionmixture, and the solution was heated at 65° C. for 12 h. The reactionmixture was cooled and diluted with 20 mL of CH₂Cl₂ and 10 mL of water.The organic layer was separated and dried over Na₂SO₄, and the solventwas removed under reduced pressure to give an oil. The residue wassubjected to purification by normal phase LC using 30-100% EtOAc-hexanesto give4-[2-(2-{[2-(tert-butoxycarbonyl-methyl-amino)-acetyl]-methyl-amino}-acetoxy)-4-methyl-pentanoyl]-piperazine-1-carboxylicacid benzyl ester (283 mg, 41% yield). LC/MS: m/z 577 (M+H)⁺ at 3.43 min(10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)).

{[2-(tert-Butoxycarbonyl-methyl-amino)-acetyl]-methyl-amino}-acetic acid1-{4-[2-(2-hydroxy-phenyl)-7-methyl-quinazolin-4-yl]-piperazine-1-carbonyl}-3-methyl-butylester

To4-[2-(2-{[2-(tert-butoxycarbonyl-methyl-amino)-acetyl]-methyl-amino}-acetoxy)-4-methyl-pentanoyl]-piperazine-1-carboxylicacid benzyl ester (208 mg, 0.49 mmol) in 1.6 mL of methanol was added 70mg of Pd/C (10% wt Pd on carbon). The reaction mixture was hydrogenatedusing a balloon of H₂ for 4 h at room temperature. The mixture was thenfiltered through Celite, and the solvent removed to give{[2-(tert-butoxycarbonyl-methyl-amino)-acetyl]-methyl-amino}-acetic acid3-methyl-1-(piperazine-1-carbonyl)-butyl ester.

The amine was taken up in 1 mL CH₂Cl₂ and treated with2-(4-chloro-7-methyl-quinazolin-2-yl)-phenol (53 mg, 0.19 mmol) and 49μL of triethylamine, and stirred at room temperature for 3 h. Thereaction mixture was diluted with 10 mL of CH₂Cl₂ and 10 mL of water.The organic layer was separated and dried over Na₂SO₄, and the solventwas removed under reduced pressure to give{[2-(tert-butoxycarbonyl-methyl-amino)-acetyl]-methyl-amino}-acetic acid1-{4-[2-(2-hydroxy-phenyl)-7-methyl-quinazolin-4-yl]-piperazine-1-carbonyl}-3-methyl-butylester. LC/MS: m/z 677.4 (M+H)⁺ at 3.25 min (10%-99% CH₃CN (0.035%TFA)/H₂O (0.05% TFA)).

[Methyl-(2-methylamino-acetyl)-amino]-acetic acid1-{4-[2-(2-hydroxy-phenyl)-7-methyl-quinazolin-4-yl]-piperazine-1-carbonyl}-3-methyl-butylester

To {[2-(tert-butoxycarbonyl-methyl-amino)-acetyl]-methyl-amino}-aceticacid1-{4-[2-(2-hydroxy-phenyl)-7-methyl-quinazolin-4-yl]-piperazine-1-carbonyl}-3-methyl-butylester (42 mg, 0.062 mmol) was added 300 μL of 1.25 M HCl in methanol atroom temperature, and the reaction mixture was stirred for 12 h. Thesolvent was removed, and the residue was purified with reverse phase LCusing 10-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA) as eluent to give[methyl-(2-methylamino-acetyl)-amino]-acetic acid1-{4-[2-(2-hydroxy-phenyl)-7-methyl-quinazolin-4-yl]-piperazine-1-carbonyl}-3-methyl-butylester as the TFA salt. LC/MS: m/z 577.4 (M+H)⁺ at 2.50 min (10%-99%CH₃CN (0.035% TFA)/H₂O (0.05% TFA)).

Example 1702-(4-Fluorophenyl)-2-hydroxy-1-(4-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperazin-1-yl)ethanone

2-(4-Fluorophenyl)-2-hydroxy-1-(4-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperazin-1-yl)ethanone

2-(7-Methyl-4-(piperazin-1-yl)quinazolin-2-yl)phenol hydrochloride(prepared analogously to2-(7-Methyl-4-piperazin-1-yl-quinazolin-2-yl)-phenol, oxalate salt, seeExample 130; 30 mg, 0.09 mmol), 2-(4-fluorophenyl)-2-hydroxyacetic acid(20 mg, 0.12 mmol), triethylamine (37.5 μL, 0.27 mmol) and HATU (45 mg,0.12 mmol) were stirred in DMF (1 mL) overnight. Purification viapreparative reverse phase HPLC (10-99% CH₃CN (0.035% TFA)/H₂O (0.05%TFA)) gave2-(4-fluorophenyl)-2-hydroxy-1-(4-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperazin-1-yl)ethanoneas the TFA salt. LC/MS: m/z 473.1 (M+H)⁺ at 2.63 min (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)).

Example 1712-(2-Isopropyl-5-methylcyclohexyloxy)-1-(4-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperazin-1-yl)ethanone

2-(2-Isopropyl-5-methylcyclohexyloxy)-1-(4-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperazin-1-yl)ethanone

To a solution of 2-(7-methyl-4-(piperazin-1-yl)quinazolin-2-yl)phenol(30 mg, 0.09 mmol) in DMF (1 mL) was added of triethylamine (25 μL)followed by the dropwise addition of2-(2-isopropyl-5-methylcyclohexyloxy)acetyl chloride (21 μL, 0.09 mmol)at 0° C. The reaction was warmed to room temperature, and purificationusing reverse phase HPLC (10-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA))gave2-(2-isopropyl-5-methylcyclohexyloxy)-1-(4-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperazin-1-yl)ethanoneas the TFA salt. LC/MS: m/z 517.5 (M+H)⁺ at 3.49 min (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)).

Example 172(R)-2-Hydroxy-1-{3-hydroxymethyl-4-[2-(2-hydroxy-phenyl)-7-methyl-quinazolin-4-yl]-piperazin-1-yl}-4-methyl-pentan-1-one

(R)-2-Hydroxy-1-{3-hydroxymethyl-4-[2-(2-hydroxy-phenyl)-7-methyl-quinazolin-4-yl]-piperazin-1-yl}-4-methyl-pentan-1-one

To3-hydroxymethyl-4-[2-(2-hydroxy-phenyl)-7-methyl-quinazolin-4-yl]-piperazine-1-carboxylicacid benzyl ester (200 mg, 0.41 mmol) in 1.7 mL of methanol was added 39mg of Pd/C (10% weight Pd on carbon). The reaction mixture was subjectedto hydrogenation using a H₂ balloon for 3 h. The reaction mixture wasfiltered through Celite and the solvent was removed to give2-[4-(2-hydroxymethyl-piperazin-1-yl)-7-methyl-quinazolin-2-yl]-phenol.This amine was treated with (R)-2-hydroxy-4-methyl-pentanoic acid (60mg, 0.45 mmol), BOP (200 mg, 0.45 mmol) and 115 μL of triethylamine in1.6 mL of DMF at room temperature for 12 h. The reaction mixture wasdiluted with 20 mL of CH₂Cl₂ and 20 mL of water, and the organic layerwas separated and dried over Na₂SO₄. The solvent was removed underreduced pressure, and the residue was subjected to purification using60-100% EtOAc-hexanes to give(R)-2-hydroxy-1-{3-hydroxymethyl-4-[2-(2-hydroxy-phenyl)-7-methyl-quinazolin-4-yl]-piperazin-1-yl}-4-methyl-pentan-1-one.LC/MS: m/z 465 (M+H)⁺ at 2.77 min (10%-99% CH₃CN (0.035% TFA)/H₂O (0.05%TFA)).

Example 173(R)-3-Hydroxy-1-(4-(2-(2-hydroxyphenyl)quinazolin-4-yl)piperazin-1-yl)butan-1-one

(R)-3-Hydroxy-1-(4-(2-(2-hydroxyphenyl)quinazolin-4-yl)piperazin-1-yl)butan-1-one

A solution of 2-(4-(piperazin-1-yl)quinazolin-2-yl)phenol (70 mg, 0.23mmol) in DMF (0.5 mL) was added to (R)-3-hydroxybutanoic acid (31 mg,0.30 mmol). Then, triethylamine (63 μL) was added, followed by asolution of HATU (113 mg) in 0.5 mL DMF at room temperature. Thereaction was stirred overnight. Purification using reverse phase HPLC(10-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)) gave(R)-3-hydroxy-1-(4-(2-(2-hydroxyphenyl)quinazolin-4-yl)piperazin-1-yl)butan-1-oneas the TFA salt. LC/MS: m/z 393.1 (M+H)⁺ at 2.03 min (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)).

Example 1742-Hydroxy-1-(4-(2-(2-hydroxyphenyl)quinazolin-4-yl)piperazin-1-yl)pentan-1-one

2-Hydroxy-1-(4-(2-(2-hydroxyphenyl)quinazolin-4-yl)piperazin-1-yl)pentan-1-one

A solution of 2-(4-(piperazin-1-yl)quinazolin-2-yl)phenol (70 mg, 0.23mmol) in DMF (0.5 mL) was added to 2-hydroxypentanoic acid (35 mg, 0.30mmol). This was followed by the addition of triethylamine (63 μL) and asolution of HATU (113 mg) in 0.5 mL DMF at room temperature. Thereaction was stirred overnight. Purification using reverse phase HPLC(10-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)) gave2-hydroxy-1-(4-(2-(2-hydroxyphenyl)quinazolin-4-yl)piperazin-1-yl)-2-methylbutan-1-oneas the TFA salt. LC/MS: m/z 407.5 (M+H)⁺ at 2.41 min (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)).

Example 1751-(4-(2-(2-Hydroxyphenyl)-7-methylquinazolin-4-yl)piperazin-1-yl)-3-(piperidin-1-yl)propan-1-one

1-(4-(2-(2-Hydroxyphenyl)-7-methylquinazolin-4-yl)piperazin-1-yl)-3-(piperidin-1-yl)propan-1-one

To 2-(7-methyl-4-(piperazin-1-yl)quinazolin-2-yl)phenol (53 mg, 0.17mmol) was added sequentially 3-(piperidin-1-yl)propanoyl chloride (33mg, 0.19 mmol) in 28 μL of CH₂Cl₂ and triethylamine (28 μL, 0.2 mmol).The mixture was stirred at 0° C. for 20 minutes After adding H₂O andCH₂Cl₂, the phases were separated, and the organic layer was dried overNa₂SO₄ and concentrated under vacuum. Purification using preparativereverse phase HPLC with 10-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA) gave1-(4-(2-(2-hydroxyphenyl)-7-methylquinazolin-4yl)piperazin-1-yl)-3-(piperdin-1-yl)propan-1-oneas the bis TFA salt. LC/MS: m/z 460.5 (M+H)⁺ at 2.33 min (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)).

Example 176(2R,3R)-2-Hydroxy-1-(4-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperazin-1-yl)-3-methylpentan-1-one

(2R,3R)-2-Hydroxy-1-(4-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperazin-1-yl)-3-methylpentan-1-one

To 2-(7-methyl-4-(piperazin-1-yl)quinazolin-2-yl)phenol (su mg, 0.25mmol) in 800 μL of CH₂Cl₂ was added sodium of(2R,3R)-2-hydroxy-3-methyl-pentanoate (50 mg, 0.33 mmol), BOP (144 mg,0.33 mmol), and triethylamine (52 μL, 0.38 mmol). The reaction mixturewas stirred at room temperature for 2 h. After adding H₂O and CH₂Cl₂,the layers were separated, and the organic layer was dried over Na₂SO₄and concentrated. Purification via preparative reverse phase HPLC using10-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA) gave(2R,3R)-2-hydroxy-1-(4-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperazin-1-yl)-3-methylpentan-1-oneas the TFA salt. LC/MS: m/z 435.5 (M+H)⁺ at 2.62 min (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)).

Example 177(S)-3,3,3-Trifluoro-2-hydroxy-1-(4-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperazin-1-yl)propan-1-one

(S)-3,3,3-Trifluoro-Z-hydroxy-1-(4-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperazin-1-yl)propan-1-one

A mixture of 2-(7-methyl-4-(piperazin-1-yl)quinazolin-2-yl)phenol (64mg, 0.2 mmol), (S)-3,3,3-trifluoro-2-hydroxypropanoic acid (29 mg, 0.2mmol), HATU (76 mg, 0.2 mmol) and triethylamine (28 μL, 0.2 mmol) in DMF(1 mL) was stirred at room temperature overnight. Purification viapreparative HPLC (10-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)) gave(S)-3,3,3-trifluoro-2-hydroxy-1-(4-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperazin-1-yl)propan-1-oneas the TFA salt. LC/MS: m/z 447.1 (M+H)⁺ at 2.53 min (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)).

Example 1782-(Trifluoromethyl)-2-hydroxy-1-(4-(2-(2-hydroxyphenyl)quinazolin-4-yl)piperazin-1-yl)propan-1-one

2-(Trifluoromethyl)-2-hydroxy-1-(4-(2-(2-hydroxyphenyl)quinazolin-4-yl)piperazin-1-yl)propan-1-one

A solution of 2-(4-(piperazin-1-yl)quinazolin-2-yl)phenol (70 mg, 0.23mmol) in DMF (0.5 mL) was added to2-(trifluoromethyl)-2-hydroxypropanoic acid (47.0 mg, 0.297 mmol). Then,triethylamine (63 μL) was added, followed by a solution of HATU (113 mg)in 0.5 mL DMF at room temperature. The reaction was stirred overnight.Purification using reverse phase HPLC (10-99% CH₃CN (0.035% TFA)/H₂O(0.05% TFA)) gave2-(trifluoromethyl)-2-hydroxy-1-(4-(2-(2-hydroxyphenyl)quinazolin-4-yl)piperazin-1-yl)propan-1-oneas the TFA salt. LC/MS: m/z 447.3 (M+H)⁺ at 2.50 min (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)).

Example 1793-Chloro-2-hydroxy-1-(4-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperazin-1-yl)propan-1-one

3-Chloro-2-hydroxy-1-(4-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperazin-1-yl)propan-1-one

A mixture of 2-(7-methyl-4-(piperazin-1-yl)quinazolin-2-yl)phenol (121mg, 0.38 mmol), 3-chloro-2-hydroxypropanoic acid (61 mg, 0.49 mmol), BOP(217 mg, 0.49 mmol), and triethylamine (79 μL, 0.56 mmol) in 1.2 mL ofCH₂Cl₂ was stirred at room temperature for 1 h. The reaction was washedwith water and the organic layer was dried over Na₂SO₄ and concentrated.Purification via preparative reverse phase HPLC using 10-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA) gave3-chloro-2-hydroxy-1-(4-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperazin-1-yl)propan-1-oneas the TFA salt. LC/MS: m/z 427.2 (M+H)⁺ at 2.59 min (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)).

Example 2011-(2-(2-Hydroxyphenyl)-7-methylquinazolin-4-yl)-N-((pyridin-3-yl)methyl)piperidine-3-carboxamide

Piperidine-3-carboxylic acid

To a solution of 1-(tert-butoxycarbonyl)piperidine-3-carboxylic acid(500 mg, 2.18 mmol) in CH₂Cl₂ (10 mL) was added TFA (5 ml). The reactionmixture was stirred for an hour. Excess TFA was removed under reducedpressure, and the piperidine-3-carboxylic acid was used withoutneutralization for the next step. LC/MS: m/z 1303 (M+H)⁺ at 0.35 min(10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)).

1-(2-(2-Hydroxyphenyl)-7-methylquinazolin-4-yl)piperidine-3-carboxylicacid

To a solution of 2-(4-chloro-7-methylquinazolin-2-yl)phenol (0.449 mg,1.66 mmol) in CH₂Cl₂ was added 5 equivalents of triethylamine followedby the addition of piperidine-3-carboxylic acid as a TFA salt. Thereaction was stirred for 2 hours and quenched with water. The layerswere separated, and the organic extracts were dried over MgSO₄,filtered, and concentrated to give1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidine-3-carboxylicacid which was used without further purification. LC/MS: m/z 364.3(M+H)⁺ at 2.22 min (10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)).

1-(2-(2-Hydroxyphenyl)-7-methylquinazolin-4-yl)-N-((pyridin-3-yl)methyl)piperidine-3-carboxamide

A solution of1-(2-(2-hydroxyphenyl)-7-methylquinazolln-4-yl)piperidine-3-carboxylicacid (45 mg, 0.12 mmol), (pyridin-3-yl)methanamine (14 μL, 0.136 mmol)and triethylamine (25 mg, 35 μL, 0.25 mmol) in 500 μL DMF was cooled to0° C., and HATU (57 mg, 0.15 mmol) was added. The reaction was warmed toroom temperature, stirred overnight and purified by reverse phase HPLC(10-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)) giving1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)-N-((pyridin-3-yl)methyl)piperidine-3-carboxamideas the TFA salt. LC/MS: m/z 454.5 (M+H)⁺ at 1.87 min (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)).

Example 203 (R)-Tetrahydrofuran-3-yl(S)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-3-ylcarbamate

Benzyl(S)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-3-ylcarbamate

To a solution of 2-(4-chloro-7-methylquinazolin-2-yl)phenol (1.15 g,4.26 mmol) in CH₂Cl₂ (25 mL) at 0° C. under inert atmosphere was slowlyadded a solution of benzyl (S)-piperidin-3-ylcarbamate (1.0 g, 4.26mmol) and triethylamine (1.18 mL, 8.52 mmol) in CH₂Cl₂ (10 mL). Thereaction was allowed to warm to room temperature and was then quenchedwith water. The mixture was extracted with CH₂Cl₂ and the organic layerswere combined, dried over MgSO₄, and concentrated to obtain benzyl(S)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-3-ylcarbamate(2.03 g). This material was used without further purification. LC/MS:m/z 469.1 (M+H)⁺ at 2.86 min (10%-99% CH₃CN (0.035% TFA)/H₂O (0.05%TFA))

2-(4-((S)-3-Aminopiperidin-1-yl)-7-methylquinazolin-2-yl)phenol

Pd/C (175 mg, 10% weight Pd on carbon) was added to a round bottom flaskand the flask was flushed with N₂. To this flask was then added MeOH (10mL). After purging the flask again with N₂,(S)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-3-ylcarbamate(1.75 g, 3.74 mmol) dissolved in EtOAc (60 mL) and MeOH (50 mL) wasadded. After flushing the flask 3 times with N₂, and evacuating it undervacuum, H₂ was passed through the vigorously stirring mixture for 4 huntil hydrogenation was complete. The mixture was filtered through a padof Celite. The filtrate was concentrated to afford2-(4-((S)-3-aminopiperidin-1-yl)-7-methylquinazolin-2-yl)phenol (0.62 g,50%). LC/MS: m/z 335.5 (M+H)⁺ at 1.50 min (10%-99% CH₃CN (0.035%TFA)/H₂O (0.05% TFA)).

(R)-Tetrahydrofuran-3-yl(S)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-3-ylcarbamate

2-(4-((S)-3-Aminopiperidin-1-yl)-7-methylquinazolin-2-yl)phenol (50 mg,0.15 mmol), (R)-tetrahydrofuran-3-yl chloroformate (22.6 mg, 0.15 mmol)and triethylamine (30 mg, 0.3 mmol) were stirred in DMF (1 mL) at 0° C.After allowing the reaction to warm to room temperature, it was purifiedvia reverse phase HPLC (10-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)) togive (R)-tetrahydrofuran-3-yl(S)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-3-ylcarbamateas the TFA salt. LC/MS: m/z 449.3.5 (M+H)⁺ at 1.52 min (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)).

Example 204 (S)-Tetrahydrofuran-3-yl(S)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-3-ylcarbamate

(S)-Tetrahydrofuran-3-yl(S)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-3-ylcarbamate

2-(4-((S)-3-Aminopiperidin-1-yl)-7-methylquinazolin-2-yl)phenol (50 mg,0.15 mmol), (S)-tetrahydrofuran-3-yl chloroformate (22.6 mg, 0.15 mmol),and triethylamine (30 mg, 0.3 mmol) were stirred in DMF (1 mL) at 0° C.After allowing the reaction to warm to room temperature it was purifiedvia reverse phase HPLC (10-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)) toafford (S)-tetrahydrofuran-3-yl(S)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-3-ylcarbamateas the TFA salt. LC/MS: m/z 449.3 (M+H)⁺ at 2.33 min (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA))

Example 205(2R)-Tetrahydro-N—((S)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-3-yl)furan-2-carboxamide

(2R)-Tetrahydro-N—((S)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-3-yl)furan-2-carboxamide

2-(4-((S)-3-Aminopiperidin-1-yl)-7-methylquinazolin-2-yl)phenol (50 mg,0.15 mmol), (R)-tetrahydrofuran-2-carboxylic acid (22.6 mg, 0.195 mmol),triethylamine (30 mg, 0.3 mmol), and HATU (74.14 mg, 0.195 mmol) werestirred at room temperature in DMF for 1 h. Purification via reversephase HPLC (10-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)) gave(2R)-tetrahydro-N—((S)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-3-yl)furan-2-carboxamideas the TFA salt. LC/MS: m/z 433.3 (M+H)⁺ at 2.33 min (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)).

Example 206(2R)-Tetrahydro-N—((R)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-3-yl)furan-2-carboxamide

tert-Butyl(R)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-3-ylcarbamate

To a solution of 2-(4-chloro-7-methylquinazolin-2-yl)phenol (0.5 g, 1.84mmol) in CH₂Cl₂ (10 mL) at 0° C. was added dropwise a solution oftert-butyl (R)-piperidin-3-ylcarbamate (0.37 g, 1.84 mmol) in CH₂Cl₂ (5mL), then triethylamine (0.51 μL, 3.68 mmol). The mixture was allowed towarm to room temperature and was stirred for 3 h. After quenching withwater, it was extracted with CH₂Cl₂. The organic layers were combined,dried over MgSO₄, and concentrated. Purification via silica gelchromatography using 5:1 CH₂Cl₂: hexanes gave tert-butyl(R)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-3-ylcarbamate(0.54 g, 68%). LC/MS: m/z 435.5 (M+H)⁺ at 2.80 min (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)).

2-(4-((R)-3-Aminopiperidin-1-yl)-7-methylquinazolin-2-yl)phenol

tert-Butyl(R)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-3-ylcarbamate(0.54 g, 1.24 mmol) was dissolved in CH₂Cl₂ (15 mL) followed by theaddition of TFA (8 mL). The reaction was stirred for 1.5 h, and thesolvents were evaporated to an oily liquid which was diluted with CH₂Cl₂and neutralized with a 1 M aqueous NaOH solution. The organic layer wasseparated, and the aqueous layer was washed two times with CH₂Cl₂. Afterdrying the combined organic phases over MgSO₄, they were filtered, andconcentrated to afford2-(4-((R)-3-aminopiperidin-1-yl)-7-methylquinazolin-2-yl)phenol as asolid (0.354 g, 85%). LC/MS: m/z 335.7 (M+H)⁺ at 1.42 min (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)).

(2R)-Tetrahydro-N—((R)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-3-yl)furan-2-carboxamide

2-(4-((R)-3-Aminopiperidin-1-yl)-7-methylquinazolin-2-yl)phenol (50 mg,0.15 mmol), (R)-tetrahydrofuran-2-carboxylic acid (22.6 mg, 0.15 mmol),triethylamine (30 mg, 0.3 mmol), and HATU (74.14 mg, 0.195 mmol) werestirred at room temperature in DMF for 1 h. Purification via reversephase HPLC (10-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)) gave(2R)-tetrahydro-N—((R)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-3-yl)furan-2-carboxamideas the TFA salt. LC/MS: m/z 433.3 (M+H)⁺ at 2.34 min (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)).

Example 207 (R)-Tetrahydrofuran-3-yl(R)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-3-ylcarbamate

(R)-Tetrahydrofuran-3-yl(R)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-3-ylcarbamate

A solution of2-(4-((R)-3-aminopiperidin-1-yl)-7-methylquinazolin-2-yl)phenol (50 mg,0.15 mmol) in DMF (0.5 mL) was cooled to 0° C. Then, a solution oftriethylamine (30 mg, 0.3 mmol) and (R)-tetrahydrofuran-3-ylchloroformate (22.6 mg, 0.15 mmol) in DMF (0.5 mL) was added dropwise.The mixture was allowed to warm to room temperature over a period of 30min before it was purified using reverse phase HPLC (10-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)) to obtain (R)-tetrahydrofuran-3-yl(R)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-3-ylcarbamateas the TFA salt. LC/MS: m/z 449.5 (M+H)⁺ at 2.34 min (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)).

Example 208 (S)-Tetrahydrofuran-3-yl(R)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-3-ylcarbamate

(S)-Tetrahydrofuran-1-yl(R)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-3-ylcarbamate

To a solution of2-(4-((R)-3-aminopiperidine-1-yl)-7-methylquinazolin-2-yl)phenol (50 mg,0.15 mmol) in DMF (0.5 mL) was cooled to 0° C. A solution of(S)-tetrahydrofuran-3-yl chloroformate (22.6 mg, 0.15 mmol) in DMF (0.5mL) was then added, followed by triethylamine (30 mg, 0.3 mmol). Themixture was allowed to warm to room temperature over a period of 30 minbefore it was purified using reverse phase HPLC (10-99% CH₃CN (0.035%TFA)/H₂O (0.05% TFA)) to obtain (S)-tetrahydrofuran-3-yl(R)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-3-ylcarbamateas the TFA salt. LC/MS: m/z 449.5 (M+H)⁺ at 2.33 min (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)).

Example 209(2S)-Tetrahydro-N-((1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-3-yl)methyl)furan-2-carboxamide

3-(Benzyloxycarbonylamino-methyl)-piperidine-1-carboxylic acidtert-butyl ester

3-Aminomethyl-piperidine-1-carboxylic acid tert-butyl ester (3.6 g, 16.8mmol) was dissolved in 42 mL anhydrous CH₂Cl₂ under an N₂ atmosphere andcooled in an ice water bath. Triethylamine (4.7 mL, 33.6 mmol) was addedfollowed by the dropwise addition of benzyl chloroformate (3.55 mL, 25.2mmol). After 16 hours, the reaction mixture was partitioned betweenCH₂Cl₂/H₂O, and separated, and the aqueous layer was extracted twicewith CH₂Cl₂. All of the organic extracts were combined, dried overNa₂SO₄, filtered, and concentrated to a light yellow oil. Purificationby silica gel chromatography using 97% CH₂Cl₂/3% MeOH gave the productas a clear, colorless oil (55%). LC/MS: m/z 349.3 (M+H)⁺ at 3.22 min(10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)).

Benzyl (piperidin-3-yl)methylcarbamate hydrochloride

Benzyl (1-(tert-butoxycarbonyl)piperidin-3-yl)methylcarbamate (3.22 g,9.25 mmol) was treated with a 4.0 M HCl solution in dioxane (11.3 mL,46.25 mmol). Formation of a white precipitate was observed. After 3 h,the reaction was complete. The solvent and excess HCl were removed underreduced pressure to obtain benzyl (piperidin-3-yl)methylcarbamatehydrochloride as a white solid. LC/MS: m/z 249.3 (M+H)⁺ at 1.28 min(10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)).

Benzyl(1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-3-yl)methylcarbamate

2-(4-Chloro-7-methylquinazolin-2-yl)phenol (1.5 g, 5.54 mmol) wassuspended in anhydrous CH₂Cl₂ (15 μL) and cooled to 0° C. under an N₂atmosphere. A mixture of benzyl (piperidin-3-yl)methylcarbamatehydrochloride (1.73 g, 6.09 mmol) in CH₂Cl₂ (20 mL), and triethylamine(23 mL, 16.67 mmol) was added dropwise. The reaction mixture was allowedto warm to room temperature, and the reaction was complete after onehour. It was then partitioned between CH₂Cl₂/H₂O, and separated, and theorganic phase was dried over Na₂SO₄, filtered, and concentrated to anorange solid. Purification by silica gel chromatography using 98%CH₂Cl₂/2% EtOAc gave benzyl(1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-3-yl)methylcarbamateas a bright yellow solid (1.75 g, 66%). LC/MS: m/z 483.5 (M+H)⁺ at 2.81min (10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)).

2-(4-(3-(Aminomethyl)piperidin-1-yl)-7-methylquinazolin-2-yl)phenol

A mixture of benzyl(1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-3-yl)methylcarbamate(1.75 g, 3.63 mmol) and EtOH/EtOAc (50 mL/20 mL) was heated to obtain ahomogeneous solution. After cooling to room temperature, Pd/C (175 mg,10% wt Pd on carbon) was added and the flask was sealed with a septum.The same flask was 3 times charged with N₂ and evacuated under vacuum.The mixture was then stirred under an H₂ atmosphere at ambient pressurefor 1 h. The product was collected by filtration through a plug ofCelite, eluting with MeOH. The filtrate was concentrated to a yellowsolid (1.26 g) to give2-(4-(3-(aminomethyl)piperidin-1-yl)-7-methylquinazolin-2-yl)phenol.LC/MS: m/z 349.3 (M+H)⁺ at 1.80 min (10%-99% CH₃CN (0.035% TFA)/H₂O(0.05% TFA)).

(2S)-Tetrahydro-N-((1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-3-yl)methyl)furan-2-carboxamide

2-(4-(3-(Aminomethyl)piperidin-1-yl)-7-methylquinazolin-2-yl)phenol (60mg, 0.17 mmol) was dissolved in anhydrous DMF (1 mL) and cooled in anice water bath. To this was added (S)-tetrahydrofuran-2-carboxylic acid(24.0 mg, 19.8 μL, 0.2 mmol), and triethylamine (50 μL, 0.34 mmol).After 5 minutes, HATU (78.3 mg, 0.2 mmol) was added in one portion, andthe reaction was allowed to warm to room temperature overnight.Purification by reverse phase HPLC (10-99% CH₃CN (0.035% TFA)/H₂O (0.05%TFA)) gave(2S)-1-tetrahydro-N-((1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-3-yl)methyl)furan-2-carboxamideas the TFA salt. LC/MS: m/z 447.5 (M+H)⁺ at 2.27 min (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)).

Example 210 (R)-Tetrahydrofuran-3-yl(1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-3-yl)methylcarbamate

(R)-Tetrahydrofuran-3-yl(1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-3-yl)methylcarbamate

2-(4-(3-(Aminomethyl)piperidin-1-yl)-7-methylquinazolin-2-yl)phenol (60mg, 0.17 mmol) was dissolved in DMF (0.5 mL) and placed into an icewater bath. (R)-tetrahydrofuran-3-yl chloroformate (31 mg, 0.2 mmol) wasdissolved in DMF (0.1 mL) and added dropwise, followed by the additionof triethylamine (50 μL, 0.34 mmol). The reaction was allowed to warm toroom temperature and was stirred overnight. Purification using reversephase HPLC (10-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)) gave(R)-tetrahydrofuran-3-yl(1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-3-yl)methylcarbamateas the TFA salt. LC/MS: m/z 463.5 (M+H)⁺ at 2.34 min (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)).

Example 211 (S)-Tetrahydrofuran-3-yl(1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-3-yl)methylcarbamate

(S)-Tetrahydrofuran-3-yl(1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-3-yl)methylcarbamate

2-(4-(3-(Aminomethyl)piperidin-1-yl)-7-methylquinazolin-2-yl)phenol (60mg, 0.17 mmol) dissolved in DMF (0.5 mL) was cooled to 0° C.(S)-Tetrahydrofuran-3-yl chloroformate (31 mg, 0.2 mmol) was dissolvedin DMF (0.1 mL) and added dropwise to the reaction mixture, followed bythe addition of triethylamine (50 μL, 0.34 mmol). The reaction wasallowed to warm to room temperature and was stirred overnight. Thereaction was purified by reverse phase HPLC (10-99% CH₃CN (0.035%TFA)/H₂O (0.05% TFA)) to obtain (S)-tetrahydrofuran-3-yl(1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-3-yl)methylcarbamateas the TFA salt. LC/MS: m/z 463.5 (M+H)⁺ at 2.34 min (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)).

Example 212N—((1-(2-(2-Hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-3-yl)methyl)cyclopropanecarboxamide

N—((1-(2-(2-Hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-3-yl)methyl)cyclopropanecarboxamide

2-(4-(3-(Aminomethyl)piperidin-1-yl)-7-methylquinazolin-2-yl)phenol (60mg, 0.17 mmol) was dissolved in DMF (0.5 mL) and cooled to 0° C.Cyclopropanecarbonyl chloride (15.7 mg, 0.2 mmol) was dissolved in DMF(0.1 mL) and added dropwise, followed by the addition of triethylamine(50 μL, 0.34 mmol). The reaction was allowed to warm to room temperatureand was stirred overnight. Purification using reverse phase HPLC (10-99%CH₃CN (0.035% TFA)/H₂O (0.05% TFA)) gaveN-((1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-3-yl)methyl)cyclopropanecarboxamideas the TFA salt. LC/MS: m/z 417.0 (M+H)⁺ at 2.30 min (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)).

Example 213(2R)—N—(1-(2-(2-Chloro-6-hydroxyphenyl)quinazolin-4-yl)piperidin-4-yl)-tetrahydrofuran-2-carboxamide

3-Chloro-2-(4-chloroquinazolin-2-yl)phenol

To a solution of 4-chloro-2-(2-chloro-6-methoxyphenyl)quinazoline (0.3g, 0.98 mmol) in CH₂Cl₂ at −78° C. was added 5 equivalents of 1 M BBr₃solution (4.9 mL, 4.9 mmol) in CH₂Cl₂. The reaction was complete after30 minutes After allowing it to warm to room temperature, the reactionmixture was quenched with aqueous NaHCO₃ to pH 7, the layers wereseparated and the aqueous layer was extracted with CH₂Cl₂. The combinedorganic extracts were dried over MgSO₄, filtered, and concentrated.Purification via silica gel chromatography using 2:1 CH₂Cl₂:hexanesyielded 3-chloro-2-(4-chloroquinazolin-2-yl)phenol (0.17 g, 60%). LC/MS:m/z 291.1 (M+H)⁺ at 3.16 min (10%-99% CH₃CN (0.035% TFA)/H₂O (0.05%TFA)).

(2R)—N-(1-(2-(2-Chloro-6-hydroxyphenyl)quinazolin-4-yl)piperidin-4-yl)-tetrahydrofuran-2-carboxamide

At 0° C., to a solution of 3-chloro-2-(4-chloroquinazolin-2-yl)phenol(42 mg, 0.144 mmol) in CH₂Cl₂ was added triethylamine (80 μL, 0.58 mmol)followed by the addition of(R)-tetrahydro-N-(piperidin-4-yl)furan-2-carboxamide a oxalate. Afterallowing the reaction to warm to room temperature it was purified viareverse phase HPLC (10-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)) to afford(2R)—N-(1-(2-(2-chloro-6-hydroxyphenyl)quinazolin-4-yl)piperidin-4-yl)-tetrahydrofuran-2-carboxamideas the TFA salt. LC/MS: m/z 453.5 (M+H)⁺ at 1.98 min (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)).

Example 214 (R)-Tetrahydrofuran-3-yl((S)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-3-yl)methylcarbamate

Method 1

Benzyl ((S)-1-(tert-butoxycarbonyl)piperidin-3-yl)methylcarbamate

(S)-tert-Butyl 3-(aminomethyl)piperidine-1-carboxylate (1.00 g, 4.67mmol) was dissolved in 14 mL anhydrous CH₂Cl₂ under an N₂ atmosphere andcooled to 0° C. Triethylamine (1.30 mL, 945 mg, 9.34 mmol) was addedfollowed by the dropwise addition of benzyl chloroformate (0.99 mL, 1.20g, 7.00 mmol). After 16 h, the reaction mixture was partitioned betweenH₂O and CH₂Cl₂, and separated, and the aqueous layer was extracted twicewith CH₂Cl₂. The organic layers were combined, dried over Na₂SO₄,filtered, and concentrated to a light yellow oil. Purification viasilica gel chromatography using 97% CH₂Cl₂/3% MeOH gave benzyl((S)-1-(tert-butoxycarbonyl)piperidin-3-yl)methylcarbamate as a clear,colorless oil (895 mg, 55%). LC/MS: m/z 349.5 (M+H)⁺ at 3.21 min(10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)).

Benzyl((S)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-3-yl)methylcarbamate

Benzyl ((S)-1-(tert-butoxycarbonyl)piperidin-3-yl)methylcarbamate(895mg, 2.57 mmol) was treated with a 4.0 M HCl solution in dioxane (3.2 mL,12.85 mmol) Formation of a white precipitate was observed. After 3 h,complete conversion of starting material was seen by TLC. The solventand excess HCl were removed under reduced pressure to obtain benzyl((R)-piperidin-3-yl)methylcarbamate hydrochloride as a white solid. Thissolid was suspended in DMF/CH₂Cl₂ (3 mL/3 mL), followed by the additionof 2-(4-chloro-7-methylquinazolin-2-yl)phenol (696 mg, 2.57 mmol), andtriethylamine (1.8 mL, 1.3 g, 12.85 mmol). The mixture was stirred atroom temperature under an N₂ atmosphere for 16 h. The reaction was thenpartitioned between H₂O/CH₂Cl₂, and separated and the aqueous layer wasextracted twice with CH₂Cl₂. The combined organic layers were dried overNa₂SO₄, filtered, and concentrated under reduced pressure. Purificationvia silica gel chromatography using 0-5% MeOH in CH₂Cl₂ gave benzyl((S)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-3-yl)methylcarbamateas a thick yellow oil (610 mg, 49%). LC/MS: m/z 483.3 (M+H)⁺ at 2.83 min(10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)).

2-(4-((S)-3-(Aminomethyl)piperidin-1-yl)-7-methylquinazolin-2-yl)phenol

To a mixture of benzyl((S)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-3-yl)methylcarbamate(610 mg, 1.26 mmol) and EtOH (15 mL) in a round bottom flask was addedPd/C (61 mg, 10% wt Pd on carbon) and the flask was sealed with aseptum. The atmosphere in the flask was evacuated, purged with N₂, andequipped with a balloon charged with H₂. The mixture was then stirredunder an H₂ atmosphere at ambient pressure for 3 h. After filtrationthrough a plug of Celite, using MeOH as the eluting solvent, thereaction mixture was concentrated to a yellow solid2-(4-((S)-3-(aminomethyl)piperidin-1-yl)-7-methylquinazolin-2-yl)phenol(441 mg). LC/MS: nm/z 349.3 (M+H)⁺ at 1.52 min (10%-99% CH₃CN (0.035%TFA)/H₂O (0.05% TFA)). ¹H NMR (400 MHz, DMSO-d6) δ 8.43-8.45 (m, 1H),7.95 (d, J=8.5 Hz, 1H), 7.64 (s, 1H), 7.35-7.39 (m, 2H), 6.92-6.96 (m,2H), 4.52 (d, J=12.5 Hz, 1H), 4.41 (d, J=13.2 Hz, 1H), 3.26-3.29 (m,2H), 3.02-3.08 (m, 1H), 2.55-2.61 (m, 1H), 2.45-2.48 (m, 1H), 1.84-1.91(m, 2H), 1.65-1.77 (m, 3H), 1.24-1.36 (m, 1H) ppm.

(R)-Tetrahydrofuran-3-yl((S)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-3-yl)methylcarbamate

Method A

2-(4-((S)-3-(Aminomethyl)piperidin-1-yl)-7-methylquinazolin-2-yl)phenol(60 mg, 0.17 mmol) was dissolved in anhydrous DMF (1 mL) and cooled to0° C., and (R)-tetrahydrofuran-3-yl chloroformate (31 mg, 0.2 mmol)dissolved in DMF (100 μL) was added dropwise followed by triethylamine(35 mg, 48 μL, 0.34 mmol). The reaction was allowed to warm to roomtemperature. The reaction was complete after two hours. Purificationusing reverse phase HPLC (10-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA))gave (R)-tetrahydrofuran-3-yl((S)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-3-yl)methylcarbamateas the TFA salt. LC/MS: m/z 463.5 (M+H)⁺ at 2.32 min (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)).

Method B

2-(4-((S)-3-(Aminomethyl)piperidin-1-yl)-7-methylquinazolin-2-yl)phenol(127 mg, 0.364 mmol) was dissolved in 5 mL anhydrous DMF and cooled to0° C., and a solution of (R)-tetrahydrofuran-3-yl chloroformate (65.4mg, 0.436 mmol) in 200 μL DMF was added dropwise followed by theaddition of triethylamine (74 mg, 0.10 mL, 0.73 mmol). The reaction wasallowed to warm to room temperature. The reaction was complete after twohours. The mixture was partitioned between H₂O and CH₂Cl₂, andseparated, and the aqueous layer was extracted twice with CH₂Cl₂. Thecombined organic phases were dried over Na₂SO₄, filtered, andconcentrated to a yellow solid. Purification via silica gelchromatography using 98% CH₂Cl₂/2% MeOH gave (R)-tetrahydrofuran-3-yl((S)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-3-yl)methylcarbamateas an off white solid (116 mg, 69%). LC/MS: m/z 463.5 (M+H)⁺ at 2.37 min(10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)).

¹H NMR (400 MHz, DMSO-d6) δ 8.41-8.43 (m, 1H), 7.86 (d, J=8.5 Hz, 1H),7.65 (s, 1H), 7.33-7.44 (m, 3H), 6.90-6.95 (m, 2H), 5.11 (dd, J=6.2, 4.6Hz, 1H), 4.38 (t, J=14.5 Hz, 2H), 3.68-3.79 (m, 3H), 3.60-3.63 (m, 1H),3.28-3.31 (m, 1H), 2.98-3.07 (m, 3H), 2.50 (s, 3H), 2.06-2.15 (m, 1H),1.85-1.91 (m, 4H), 1.70 (d, J=12.9 Hz, 1H), 1.24-1.37 (m, 1H) ppm.

(R)-Tetrahydrofuran-3-yl((S)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-3-yl)methylcarbamatehydrochloride

(R)-Tetrahydrofuran-3-yl((S)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-3-yl)methylcarbamate(116 mg, 0.251 mmol) was suspended in 8 mL anhydrous CH₂Cl₂ and gentlyheated until an homogenous solution was formed. After the reaction wascooled to room temperature, a 2.0 M solution of HCl in Et₂O (0.126 mL,0.251 mmol) was added in one portion. The reaction mixture was dilutedwith 25 mL Et₂O, and the product precipitated from solution. Thereaction was stirred for an additional 30 minutes before the solid wasfiltered and dried to obtain (R)-tetrahydrofuran-3-yl((S)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-3-yl)methylcarbamatehydrochloride as a light yellow solid (99 mg, 70%). LC/MS: m/z 463.5(M+H)⁺ at 2.37 min (10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)). ¹H NMR(400 MHz, DMSO-d6) δ 8.22 (d, J=7.7 Hz, 1H), 7.95 (d, J=8.5 Hz, 1H),7.75 (s, 1H), 7.42-7.49 (m, 3H), 6.97-7.08 (m, 2H), 5.08 (dd, J=6.1, 4.6Hz, 1H), 4.52-4.54 (m, 2H), 3.66-3.78 (m, 3H), 3.58-3.60 (m, 1H), 3.48(t, J=10.7 Hz, 1H), 3.23 (t, J=11.5 Hz, 1H), 3.00 (t, J=6.3 Hz, 2H),2.53 (s, 3H), 2.05-2.14 (m, 1H), 1.80-1.91 (m, 4H), 1.72 (d, J=9.0 Hz,1H), 1.34-1.43 (m, 1H) ppm.

Method 2

tert-Butyl((S)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-3-yl)methylcarbamate

To a solution of 2-(4-chloro-7-methylquinazolin-2-yl)phenol (0.478 g,1.76 mmol) in CH₂Cl₂ was added triethylamine (0.98 mL, 0.712 g, 7.04mmol), and the mixture was cooled to 0° C. To the reaction mixture wasadded tert-butyl ((R)-piperidin-3-yl)methylcarbamate oxalate (preparedanalogously to 2-(7-Methyl-4-piperazin-1-yl-quinazolin-2-yl)-phenol,oxalate salt, see Example 130; 700 mg, 2.3 mmol). The reaction wasallowed to warm to room temperature and was stirred overnight. Thereaction was quenched with water, and the aqueous layer was extractedwith CH₂Cl₂. The combined organic layers were dried over MgSO₄,filtered, and concentrated. Purification via silica gel chromatographyusing 0-2% EtOAc in CH₂Cl₂ gave tert-butyl((S)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-3-yl)methylcarbamate(700 mg, 88%). LC/MS: nm/z 449.5 (M+H)⁺ at 2.77 min (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)).

2-(4-((S)-3-(Aminomethyl)piperidin-1-yl)-7-methylquinazolin-2-yl)phenol

Totert-Butyl-((S)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-3-yl)methylcarbamate(700 mg, 1.56 mmol) was added 20 mL CH₂Cl₂ followed by addition of 7 mLof TFA. After the reaction was stirred for 1 hour it was neutralizedwith a 1.0 M aqueous NaOH solution. The mixture was partitioned betweenH₂O and CH₂Cl₂, and separated, and the aqueous layer was extracted withCH₂Cl₂. The combined organic layers were dried over MgSO₄, filtered, andconcentrated to yield2-(4-((S)-3-(aminomethyl)piperidin-1-yl)-7-methylquinazolin-2-yl)phenol(400 mg, 74%). LC/MS: m/z 349.3 (M+H)⁺ at 1.52 min (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)).

(R)-Tetrahydrofuran-3-yl((S)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-3-yl)methylcarbamate

To a solution of2-(4-((S)-3-(aminomethyl)piperidin-1-yl)-7-methylquinazolin-2-yl)phenol(210 mg, 0.6 mmol) in DMF at 0° C. were added (R)-tetrahydrofuran-3-ylchloroformate (0.09 g, 0.6 mmol) and triethylamine (167 μL, 1.2 mmol)simultaneously. Ten to fifteen minutes after addition, the reaction wascomplete, and quenched with water, extracted with CH₂Cl₂. The combinedorganic layers were dried over MgSO₄, filtered, and concentrated to give(R)-tetrahydrofuran-3-yl((S)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-3-yl)methylcarbamate(150 mg, 54%). LC/MS: m/z 463.5 (M+H)⁺ at 2.37 min (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)). ¹H NMR (400 MHz, DMSO-d6) δ 8.41-8.43 (m,1H), 7.86 (d, J=8.5 Hz, 1H), 7.65 (s, 1H), 7.33-7.44 (m, 3H), 6.90-6.95(m, 2H), 5.11 (dd, J=6.2, 4.6 Hz, 1H), 4.38 (t, J=14.5 Hz, 2H),3.68-3.79 (m, 3H), 3.60-3.63 (m, 1H), 3.28-3.31 (m, 1H), 2.98-3.07 (m,3H), 2.50 (s, 3H), 2.06-2.15 (m, 1H), 1.85-1.91 (m, 4H), 1.70 (d, J=12.9Hz, 1H), 1.24-1.37 (m, 1H) ppm.

Example 215 (S)-Tetrahydrofuran-3-yl((S)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-3-yl)methylcarbamate

(S)-Tetrahydrofuran-3-yl((S)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-3-yl)methylcarbamate

Method A

2-(4-((S)-3-(Aminomethyl)piperidin-1-yl)-7-methylquinazolin-2-yl)phenol(60 mg, 0.17 mmol) was dissolved in anhydrous DMF (1 mL) and cooled to0° C., and (S)-tetrahydrofuran-3-yl chloroformate (31 mg, 0.2 mmol) inDMF (100 μL) was added dropwise followed by triethylamine (35 mg, 48 μL,0.34 mmol). The reaction was allowed to warm to room temperature. Thereaction was complete after two hours. Purification using preparativeHPLC (10-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)) gave(S)-tetrahydrofuran-3-yl((S)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-3-yl)methylcarbamateas the TFA salt. LC/MS: m/z 463.5 (M+H)⁺ at 2.37 min (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)).

Method B

2-(4-((S)-3-(Aminomethyl)piperidin-1-yl)-7-methylquinazolin-2-yl)phenol(126.8 mg, 0.364 mmol) was dissolved in 5 mL anhydrous DMF and cooled to0° C., and a solution of (S)-tetrahydrofuran-3-yl chloroformate (65.4mg, 0.436 mmol) in 200 μl of DMF was added dropwise followed by theaddition of triethylamine (74 mg, 0.102 mL, 0.728 mmol). The reactionwas allowed to warm to room temperature and was complete after twohours. The mixture was partitioned between H₂O and CH₂Cl₂, separated,and the aqueous layer was extracted twice with CH₂Cl₂. The combinedorganic phases were dried over Na₂SO₄, filtered, and concentrated to ayellow solid. Purification via silica gel chromatography using 98%CH₂Cl₂/2% MeOH gave (S)-tetrahydrofuran-3-yl((S)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-3-yl)methylcarbamateas an off white solid (116 mg, 69%). LC/MS: m/z 463.5 (M+H)⁺ at 2.37 min(10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)).

Method C

To a solution of2-(4-((S)-3-(aminomethyl)piperidin-1-yl)-7-methylquinazolin-2-yl)phenol(175 mg, 0.5 mmol) in DMF at 0° C. were added (S)-tetrahydrofuran-3-ylchloroformate (75 mg, 0.5 mmol) and triethylamine (137 μL, 1.0 mmol)simultaneously. Ten to fifteen minutes after addition, the reaction wascomplete, and it was quenched with water and extracted with CH₂Cl₂Thecombined organic layers were dried over MgSO₄, filtered, andconcentrated. Purification via silica gel chromatography using 98%CH₂Cl₂/2% MeOH gave (S)-tetrahydrofuran-3-yl ((S)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-3-yl)methylcarbamate(150 mg, 54%). LC/MS: m/z 463.5 (M+H)⁺ at 2.37 min (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)).

(S)-Tetrahydrofuran-3-yl((S)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-3-yl)methylcarbamatehydrochloride

(S)-Tetrahydrofuran-3-yl((S)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-3-yl)methylcarbamate(115 mg, 0.251 mmol) was suspended in 8 mL of anhydrous CH₂Cl₂ andgently heated until an homogenous solution was formed. After cooling toroom temperature, a 2.0 M solution of HCl in Et₂O (0.126 mL, 0.251 mmol)was added in one portion. The reaction mixture was diluted with 25 mLEt₂O, and the product precipitated from the solution. The reaction wasstirred for an additional 30 minutes before the solid was filtered anddried to obtain (S)-tetrahydrofuran-3-yl((S)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-3-yl)methylcarbamatehydrochloride (108 mg, 86%) as a light yellow solid. LC/MS: m/z 463.5(M+H)⁺ at 2.37 min (10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)). ¹H NMR(400 MHz, DMSO-d6) δ 8.18 (d, J=6.6 Hz, 1H), 7.94 (d, J=8.6 Hz, 1H),7.73 (s, 1H), 7.44-7.51 (m, 2H), 7.00-7.07 (m, 2H), 5.06-5.09 (m, 1H),4.52-4.62 (m, 2H), 3.62-3.74 (m, 4H), 3.23-3.29 (m, 1H), 3.00 (d, J=6.8Hz, 2H), 2.52 (s, 3H), 2.02-2.11 (m, 1H), 1.61-2.01 (m, 4H), 1.24-1.43(m, 2H), 0.84-0.89 (m, 1H) ppm.

Example 216 (R)-Tetrahydrofuran-3-yl((R)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-3-yl)methylcarbamate

Benzyl ((R)-1-(tert-butoxycarbonyl)piperidin-3-yl)methylcarbamate

(R)-tert-Butyl 3-(aminomethyl)piperidine-1-carboxylate (1.00 g, 4.67mmol) was dissolved in 14 mL anhydrous CH₂Cl₂ under an N₂ atmosphere andcooled to 0° C. Triethylamine (1.30 mL, 945 mg, 9.34 mmol) was addedfollowed by the dropwise addition of benzyl chloroformate (0.99 mL, 1.20g, 7.00 mmol). After 16 h, the reaction was complete. The mixture waspartitioned between H₂O and CH₂Cl₂, and separated, and the aqueous layerwas extracted twice with CH₂Cl₂. The organic layers were combined, driedover Na₂SO₄, filtered, and concentrated to a light, yellow oil.Purification via silica gel chromatography using 97% CH₂Cl₂/3% MeOHgave, benzyl ((R)-1-(tert-butoxycarbonyl)piperidin-3-yl)methylcarbamateas a clear colorless oil (1.2 g, 74%). LC/MS: m/z 349.5 (M+H)⁺ at 3.21min (10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)).

Benzyl((R)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-3-yl)methylcarbamate

Benzyl ((S)-1(tert-butoxycarbonyl)piperdin-3-yl)methylcarbamate(1.2 g,3.54 mmol) was treated with 4.0 M HCl solution in dioxane (4.3 mL, 17.2mmol). Formation of a white precipitate was observed. The reaction wascomplete after three hours. The solvent and excess HCl were removedunder reduced pressure to obtain benzyl ((S)-piperidin-3-yl)methylcarbamate hydrochloride as a white solid. This solid was suspendedin DMF/CH₂Cl₂ (3 mL/3 mL), followed by the addition of2-(4-chloro-7-methylquinazolin-2-yl)phenol (958 mg, 3.54 mmol) and thentriethylamine (1.8 mL, 1.3 g, 12.85 mmol). The mixture was stirred atroom temperature under an N₂ atmosphere for 16 h. The reaction was thenpartitioned between H₂O and CH₂Cl₂, separated, and the aqueous layer wasextracted twice with CH₂Cl₂. The combined organic layers were dried overNa₂SO₄, filtered, and concentrated under reduced pressure. Purificationvia silica gel chromatography using 0-5% MeOH in CH₂Cl₂ gave benzyl((R)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-3-yl)methylcarbamateas a thick yellow oil (855 mg, 51%). LC/MS: m/z 483.5 (M+H)⁺ at 2.81 min(10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)).

2-(4-((R)-3-(Aminomethyl)piperidin-1-yl)-7-methylquinazolin-2-yl)phenol

To a mixture of benzyl((R)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-3-yl)methylcarbamate(855 mg, 1.77 mmol) and EtOH (15 mL) in a round bottom flask was addedPd/C (86 mg, 10% wt Pd on carbon) and the flask was sealed with aseptum. The atmosphere in the flask was evacuated, purged with N₂, andequipped with a balloon charged with H₂. The mixture was stirred underan H₂ atmosphere at ambient pressure for 3 h. After filtration through aplug of Celite using MeOH as the eluting solvent, the reaction mixturewas concentrated to2-(4-((R)-3-(aminomethyl)piperidin-1-yl)-7-methylquinazolin-2-yl)phenol(625 mg) as a yellow solid. LC/MS: m/z 349.3 (M+H)⁺ at 1.82 min (10%-99%CH₃CN (0.035% TFA)/H₂O (0.05% TFA)).

(R)-Tetrahydrofuran-3-yl((R)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-3-yl)methylcarbamate

Method A

2-(4-((R)-3-(Aminomethyl)piperidin-1-yl)-7-methylquinazolin-2-yl)phenol(60 mg, 0.17 mmol) was dissolved in anhydrous DMF (1 mL) and cooled to0° C., upon which (R)-tetrahydrofuran-3-yl chloroformate (31 mg, 0.2mmol) dissolved in DMF (100 μL) was added dropwise followed by theaddition of triethylamine (35 mg, 48 μL, 0.34 mmol). The reaction wasallowed to warm to room temperature, and was complete after two hours.Purification using reverse phase HPLC (10%-99% CH₃CN (0.035% TFA)/H₂O(0.05% TFA)) gave (R)-tetrahydrofuran-3-yl((R)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-3-yl)methylcarbamateas the TFA salt. LC/MS: m/z 463.5 (M+H)⁺ at 2.35 min (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)).

Method B

To a stirred solution of2-(4-((R)-3-(aminomethyl)piperidin-1-yl)-7-methylquinazolin-2-yl)phenol(150 mg, 0.43 mmol) under an N₂ atmosphere at 0° C. was addedtriethylamine (87 mg, 0.86 mmol) followed by the dropwise addition of(R)-tetrahydrofuran-3-yl chloroformate (65 mg, 0.43 mmol). The reactionwas allowed to warm to room temperature and was stirred for 2 h. Themixture was partitioned between H₂O and CH₂Cl₂ and separated, and theaqueous layer was extracted twice with CH₂Cl₂. The organic layers werecombined, dried over Na₂SO₄, filtered, and concentrated. Purificationvia silica gel chromatography using 4:1 CH₂Cl₂:EtOAc afforded(R)-tetrahydrofuran-3-yl((R)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-3-yl)methylcarbamate.LC/MS: m/z 463.5 (M+H)⁺ at 2.34 min (10%-99%.CH₃CN (0.035% TFA)/H₂O(0.05% TFA)).

(R)-Tetrahydrofuran-3-yl((R)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-3-yl)methylcarbamatehydrochloride

To a solution of (R)-tetrahydrofuran-3-yl((R)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-3-yl)methylcarbamate(0.085 g, 0.18 mmol) in 9 mL CH₂Cl₂

was added dropwise a 2.0 M HCl solution in ether (0.09 mL, 0.18 mmol).Ether (20 mL) was then added, leading to the precipitation of(R)-tetrahydrofuran-3-yl((R)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-3-yl)methylcarbamatehydrochloride which was filtered and dried (85 mg, 95%). LC/MS: m/z463.5 (M+H)⁺ at 2.33 min (10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)).

Example 217 (S)-Tetrahydrofuran-3-yl((R)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-3-yl)methylcarbamate

(S)-Tetrahydrofuran-3-yl((R)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-3-yl)methylcarbamate

Method A

2-(4-((R)-3-(Aminomethyl)piperidin-1-yl)-7-methylquinazolin-2-yl)phenol(60 mg, 0.17 mmol) was dissolved in anhydrous DMF (1 mL) and cooled to0° C., upon which (S)-tetrahydrofuran-3-yl chloroformate (31 mg, 0.2mmol) dissolved in DMF (100 μL) was added dropwise followed bytriethylamine (35 mg, 48 μL, 0.34 mmol). The reaction was allowed towarm to room temperature and was complete after 2 h. Purification byreverse phase HPLC (10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)) gave(S)-tetrahydrofuran-3-yl((R)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-3-yl)methylcarbamateas the TFA salt. LC/MS: m/z 463.5 (M+H)⁺ at 2.35 min (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)).

Method B

To a stirred solution of2-(4-((R)-3-(aminomethyl)piperidin-1-yl)-7-methylquinazolin-2-yl)phenol(200 mg, 0.57 mmol) in DMF under an N₂ atmosphere at 0° C. was addedtriethylamine (115 mg, 1.14 mmol) followed by the dropwise addition of(S)-tetrahydrofuran-3-yl chloroformate (86 mg, 0.57 mmol). The reactionwas allowed to warm to room temperature and was stirred for 2 h. Themixture was partitioned between H₂O and CH₂Cl₂ and separated, and theaqueous layer was extracted twice with CH₂Cl₂. The organic layers werecombined, dried over Na₂SO₄, filtered, and concentrated. Purificationvia silica gel chromatography using 4:1 CH₂Cl₂:EtOAc afforded(S)-tetrahydrofuran-3-yl((R)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-3-yl)methylcarbamate.LC/MS: m/z 463.5 (M+H)⁺ at 2.34 min (10%-99% CH₃CN (0.035% TFA)/H₂O(0.05% TFA)).

((S)-Tetrahydrofuran-3-yl((R)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-3-yl)methylcarbamatehydrochloride

To a solution of (S)-tetrahydrofuran-3-yl((R)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-3-yl)methylcarbamatein 12 mL CH₂Cl₂ was added dropwise 2.0 M HCl solution in ether (0.13 mL,0.25 mmol). To the solution was then added 20 mL ether leading to theprecipitation of ((S)-tetrahydrofuran-3-yl((R)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-3-yl)methylcarbamatehydrochloride which was filtered and dried (116 mg, 92%). LC/MS: m/z463.5 (M+H)⁺ at 2.33 min (10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)).

Example 218(2R)-Tetrahydro-N-(1-(2-(2-hydroxy-6-methylphenyl)-7-methylquinazolin-4-yl)piperidin-4-yl)furan-2-carboxamide

(R)-Tetrahydrofuran-2-carboxylic acid (1-benzyl-piperidin-4-yl)-amide

A solution of (R)-tetrahydro-2-furoic acid (58.5 g, 504 mmol) and oxalylchloride (86 mL, 1.0 mol) in 100 mL CH₂Cl₂ were refluxed for 2 hours ina flask equipped with a CaCl₂ guard tube. After the solution was cooledto room temperature the solvents and excess oxalyl chloride were removedby evaporation under reduced pressure. The resulting acid chloride wasdissolved in 200 mL CH₂Cl₂ and added dropwise to a solution of1-benzyl-4-amino piperidine dihydrochloride (142 g, 539 mmol) andtriethylamine (240 mL, 1.7 mol) in 300 mL CH₂Cl₂ cooled in an ice bath.The resulting mixture was stirred for 2 hours at room temperature andsubsequently washed twice with 300 mL portions of 5% aq. NaHCO₃ and 300mL saturated aq. NaCl solution, dried over Na₂SO₄, filtered, andevaporated to dryness under reduced pressure. The solid residue wastriturated with 500 mL heptanes, collected by filtration, and washedtwice with 200 mL portions of heptanes. The solid was air-dried at 45°C. to yield (R)-tetrahydrofuran-2-carboxylic acid(1-benzyl-piperidin-4-yl)-amide (128 g, 88%) as an off-white solid.¹H-NMR (300 MHz, CDCl₃): δ 7.35-7.20 (m, 5H), 6.58 (bs, 1H), 4.29 (dd,J=5.9, 8.4 Hz, 1H), 3.92-3.77 (m, 2H), 3.48 (s, 2H), 2.82-2.74 (m, 2H),2.32-2.21 (m, 1H), 2.19-1.95 (m, 3H), 1.94-1.78 (m, 4H), 1.58-1.40 (m,2H) ppm.

(R)-Tetrahydro-furan-2-carboxylic acid piperidin-4-ylamide as an oxalatesalt

(R)-Tetrahydro-furan-2-carboxylic acid (1-benzyl-piperidin-4-yl)-amide(128 g, 444 mmol) was dissolved in 300 mL ethanol and 50 mL acetic acid.Palladium on activated carbon (5 g) was added. A hydrogen pressure of 5bars was applied, and hydrogenation was continued until no more hydrogenwas consumed (about 5 days). The suspension was filtered through Celite,and the filtrate was evaporated to dryness under reduced pressure. Theresidue and oxalic acid (50 g, 555 mmol) were suspended in 500 mL2-propanol and heated to dissolve the solids. Upon cooling, the oxalatesalt of R-tetrahydro-furan-2-carboxylic acid piperidin-4-ylamidecrystallized and was collected by filtration to yield(R)-Tetrahydro-furan-2-carboxylic acid piperidin-4-ylamide as an oxalatesalt (99.0 g, 77%) as an off-white solid. ¹H-NMR (300 MHz, DMSO-d₆): δ7.84 (d, J=7.8 Hz, 1H), 5.90 (bs, 2H), 4.18-4.14 (m, 1H), 3.89-3.67 (m,3H), 3.25-3.20 (m, 2H), 2.94-2.71 (m, 2H), 2.13-2.00 (m, 1H), 1.56-1.58(m, 6H) ppm.

(2R)-Tetrahydro-N-(1-(2-(2-hydroxy-6-methylphenyl)-7-methylquinazolin-4-yl)piperidin-4-yl)furan-2-carboxamide

To a solution of 2-(4-chloro-7-methylquinazolin-2-yl)-3-methylphenol (60mg, 2.1 mmol) in DMF (1 mL) was added triethylamine (1.17 mL, 8.4 mmol)and (R)-tetrahydro-N-(piperidin-4-yl)furan-2-carboxamide as an oxalatesalt (80 mg, 2.73 mmol). This mixture was stirred for 2 h at roomtemperature before it was purified via reverse phase HPLC using 10%-99%CH₃CN (0.035% TFA)/H₂O (0.05% TFA) to afford(2R)-tetrahydro-N-(1-(2-(2-hydroxy-6-methylphenyl)-7-methylquinazolin-4-yl)piperidin-4-yl)furan-2-carboxamideas the TFA salt. LC/MS: m/z 447.5 (M+H)⁺ at 2.19 min (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)).

Example 219{1-[2-(2-Hydroxy-phenyl)-7-methyl-quinazolin-4-yl]-piperidin-4-yl}-carbamicacid tetrahydro-pyran-2-ylmethyl ester

(Tetrahydro-2H-pyran-2-yl)methyl 1H-imidazole-1-carboxylate

A mixture of (tetrahydro-2H-pyran-2-yl)methanol (369 mg, 3.18 mmol) anddi(1H-imidazol-1-yl)methanone (1.0 g, 6.36 mmol) in 0.3 M CH₃Cl (10 mL)was stirred at 50° C. for 3 h. After allowing the reaction to cool toroom temperature, the solvent was evaporated under reduced pressuregiving (tetrahydro-2H-pyran-2-yl)methyl 1H-imidazole-1-carboxylate (412mg) which was used without further purification. LC/MS: m/z 211.1 (M+H)⁺at 0.94 min (10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)).

{1-[2-(2-Hydroxy-phenyl)-7-methyl-quinazolin-4-yl]-piperidin-4-yl}-carbamicacid tetrahydro-pyran-2-ylmethyl ester

To 2-[4-(4-amino-piperidin-1-yl)-7-methyl-quinazolin-2-yl]-phenol (100mg, 0.3 mmol) in 1 mL CH₂Cl₂ was added sequentially triethylamine (62.5μL, 0.45 mmol) and imidazole-1-carboxylic acidtetrahydro-pyran-2-ylmethyl ester (94 mg, 0.45 mmol). The reactionmixture was stirred at room temperature for 12 h and at 45° C. for 3 h.The reaction mixture was cooled and diluted with water and CH₂Cl₂. Theorganic layer was separated and dried over Na₂SO₄, and the solvent wasremoved under reduced pressure to give an oil. The residue was purifiedby reverse phase HPLC using 10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)as eluent to give the desired product{1-[2-(2-hydroxy-phenyl)-7-methyl-quinazolin-4-yl]-piperidin-4-yl}-carbamicacid tetrahydro-pyran-2-ylmethyl ester as the TFA salt. LC/MS: m/z 477.4(M+H)⁺ at 2.84 min (10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)).

Example 220Tetrahydro-N-(1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-4-yl)-2H-pyran-4-carboxamide

tert-Butyl1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-4-ylcarbamate

To a cooled (0-5° C.) suspension of2-(4-chloro-7-methylquinazolin-2-yl)phenol (50.2 g, 186 mmol) indichloromethane (200 mL) was slowly added a solution of tert-butylpiperidin-4-ylcarbamate (39.0 g, 195 mmol) and triethylamine (56 mL, 390mmol) in dichloromethane (200 mL). The resulting mixture was stirredovernight at room temperature. Water (400 ml) was added, and the layerswere separated. The aqueous layer was extracted with dichloromethane(2×200 mL), and the combined organic layers were dried over sodiumsulfate, filtered, and evaporated to dryness under reduced pressure. Theresidue was purified by column chromatography (SiO₂, eluent:dichloromethane/heptanes 4:6-1:0). Two fractions were obtained: 38.7 gof tert-butyl1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-4-ylcarbamateas a yellow solid, and a less pure fraction (26.1 g) that was purifiedby recrystallization from methanol to yield tert-butyl1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-4-ylcarbamate.Both fractions were combined (17.0 g, 69%).

2-(4-(4-Aminopiperidin-1-yl)-7-methylquinazolin-2-yl)phenol

tert-Butyl1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-4-ylcarbamate(55.7 g, 128 mmol) was dissolved in dichloromethane (200 mL) andtrifluoroacetic acid (215 ml) was slowly added (careful: immediate gasevolution!). The resulting solution was stirred overnight at roomtemperature under a nitrogen atmosphere and evaporated to dryness. Tothe residue were added equal amounts of water and dichloromethane (300mL). The obtained emulsion was basified to pH 9 with 33% aq. NaOH. Theemulsion was cleared by the addition of methanol, and the layers wereseparated. The aqueous layer was extracted with dichloromethane (200mL), and the combined organic extracts were dried over sodium sulfate,filtered, and evaporated to dryness to yield crude2-(4-(4-aminopiperidin-1-yl)-7-methylquinazolin-2-yl)phenol. The crudematerial was purified by column chromatography (SiO₂, 2% methanol indichloromethane) to yield2-(4-(4-aminopiperidin-1-yl)-7-methylquinazolin-2-yl)phenol (44 g, 97%)as a yellow solid. ¹H-NMR (300 MHz, CDCl₃): δ 8.52 (dd, J=2.1, 8.1 Hz,1H), 7.77 (d, J=8.4 Hz, 1H), 7.62 (s, 1H), 7.37 (dt, J=1.5, 7.2 Hz, 1H),7.22 (dd, J=1.5, 9.0 Hz, 1H), 7.04 (dd, J=1.2, 6.9 Hz, 1H), 6.92 (dt,J=1.2, 7.2 Hz, 1H), 4.49-4.39 (m, 2H), 3.34 (dt, J=2.4, 12.2 Hz, 2H),3.12-3.02 (m, 1H), 2.54 (s, 3H), 2.09-2.00 (m, 2H), 1.68-1.55 (m, 2H),1.40-1.25 (m, 2H) ppm.

Tetrahydro-N-(1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-4-yl)-2H-pyran-4-carboxamide

To a solution of2-(4-(4-aminopiperidin-1-yl)-7-methylquinazolin-2-yl)phenol (30 mg, 0.09mmol) in DMF (1 mL) was added tetrahydro-2H-pyran-4-carboxylic acid(17.5 mg, 0.13 mmol) followed by the addition of triethylamine (25 μL,0.18 mmol) and HATU (44 mg, 0.117 mmol). The reaction was stirred for 16h, filtered, and purified by reverse phase HPLC (10%-99% CH₃CN (0.035%TFA)/H₂O (0.05% TFA)) to affordtetrahydro-N-(1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-4-yl)-2H-pyran-4-carboxamideas the TFA salt. LC/MS: m/z 447.5 (M+H)⁺ at 2.19 min (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)).

Example 2212-(Tetrahydro-2H-pyran-4-yl)-N-(1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-4-yl)acetamide

2-(Tetrahydro-2H-pyran-4-yl)-N-(1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-4-yl)acetamide

To a solution of2-(4-(4-aminopiperidin-1-yl)-7-methylquinazolin-2-yl)phenol (30 mg, 0.09mmol) in DMF (1 mL) was added 2-(tetrahydro-2H-pyran-4-yl)acetic acid(13 mg, 0.09 mmol) followed by the addition of triethylamine (25 μL,0.18 mmol) and HATU (44 mg, 0.117 mmol). The reaction was stirred for 16h, filtered, and purified by reverse phase HPLC (10%-99% CH₃CN (0.035%TFA)/H₂O (0.05% TFA)) to afford2-(tetrahydro-2H-pyran-4-yl)-N-(1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-4-yl)acetamideas the TFA salt. LC/MS: m/z 461.5 (M+H)⁺ at 2.22 min (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)).

Example 2222-(2-Isopropyl-5-methylcyclohexyloxy)-N-(1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-4-yl)acetamide

To a solution of2-(4-(4-aminopiperidin-1-yl)-7-methylquinazolin-2-yl)phenol (30 mg, 0.09mmol) in DMF (1 mL) at 0° C. was added triethylamine (25 μL, 0.18 mmol)followed by the addition of 2-(2-isopropyl-5-methylcyclohexyloxy)acetylchloride (21 mg, 0.09 mmol). The reaction was stirred for 16 h,filtered, and purified by reverse phase HPLC (10%-99% CH₃CN (0.035%TFA)/H₂O (0.05% TFA)) to afford2-(2-isopropyl-5-methylcyclohexyloxy)-N-(1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-4-yl)acetamideas the TFA salt. LC/MS: m/z 531.3 (M+H)⁺ at 3.08 min (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)).

Example 223N-(1-(2-(2-Hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-4-yl)-3-(pyridin-2-yl)propanamide

N-(1-(2-(2-Hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-4-yl)-3-(pyridin-2-yl)propanamide

To a solution of2-(4-(4-aminopiperidin-1-yl)-7-methylquinazolin-2-yl)phenol (30 mg, 0.09mmol) in DMF (1 mL) was added 3-(pyridin-2-yl)propanoic acid (20 mg,0.13 mmol) followed by the addition of triethylamine (25 μL, 0.18 mmol)and HATU (44 mg, 0.117 mmol). The reaction was stirred for 16 h,filtered, and purified by reverse phase HPLC (10%-99% CH₃CN (0.035%TFA)/H₂O (0.05% TFA)) to affordN-(1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-4-yl)-3-(pyridin-2-yl)propanamideas the TFA salt. LC/MS: m/z 468.3 (M+H)⁺ at 1.86 min (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)).

Example 224(2R)—N-(1-(6-Fluoro-2-(2-hydroxyphenyl)quinazolin-4-yl)piperidin-4-yl)-tetrahydrofuran-2-carboxamide

(2R)—N-(1-(6-Fluoro-2-(2-hydroxyphenyl)quinazolin-4-yl)piperidin-4-yl)-tetrahydrofuran-2-carboxamide

To a solution of 2-(4-chloro-6-fluoroquinazolin-2-yl)phenol (25 mg, 0.09mmol) in CH₂Cl₂ (1 mL) was added(R)-tetrahydro-N-(piperidin-4-yl)furan-2-carboxamide oxalate (33 mg,0.117 mmol), followed by the addition of triethylamine (50 μL, 0.36mmol). The reaction was stirred for 2 h before it was filtered, andpurified by reverse phase HPLC (10%-99% CH₃CN (0.035% TFA)/H₂O (0.05%TFA)) to afford(2R)—N-(1-(6-fluoro-2-(2-hydroxyphenyl)quinazolin-4-yl)piperidin-4-yl)-tetrahydrofuran-2-carboxamideas the TFA salt. LC/MS: m/z 437.1 (M+H)⁺ at 2.54 min (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)).

Example 225N-{1-[2-(2-Hydroxy-phenyl)-7-methyl-quinazolin-4-yl]-piperidin-4-yl}-3-pyridin-3-yl-propionamide

N-{1-[2-(2-Hydroxy-phenyl)-7-methyl-quinazolin-4-yl]-piperidin-4-yl}-3-pyridin-3-yl-propionamide

To 2-[4-(4-amino-piperidin-1-yl)-7-methyl-quinazolin-2-yl]-phenol (238mg, 0.71 mmol) in 2.4 mL of CH₂Cl₂ was added sequentially3-pyridin-3-yl-propionic acid (118.3 mg, 0.78 mmol), triethylamine (129μL, 0.92 mmol), and BOP (346 mg, 0.78 mmol) at room temperature. Thereaction mixture was stirred for 40 min and diluted with water andCH₂Cl₂. The organic layer was separated and dried over Na₂SO₄, and thesolvent was removed under reduced pressure to give an oil. The residuewas purified by reverse phase LC using 10%-99% CH₃CN (0.035% TFA)/H₂O(0.05% TFA) as eluent to give the desired product as the TFA salt.LC/MS: m/z 468.6 (M+H)⁺ at 2.19 min (10%-99% CH₃CN (0.035% TFA)/H₂O(0.05% TFA)).

Example 226N—(((S)-1-(2-(2-Hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-3-yl)methyl)cyclopropanecarboxamide

N—(((S)-1-(2-(2-Hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-3-yl)methyl)cyclopropanecarboxamide

2-(4-((S)-3-(Aminomethyl)piperidin-1-yl)-7-methylquinazolin-2-yl)phenol(35 mg, 0.10 mmol) was dissolved in DMF (1 mL). Cyclopropanecarboxylicacid (9.7 mg, 0.11 mmol) was added, followed by the addition oftriethylamine (28 μL, 0.2 mmol), and the mixture was cooled in an icewater bath. HATU (42 mg, 0.11 mmol) was added in one portion, and thereaction was allowed to warm to room temperature while stirring for 16h. The reaction mixture was filtered, and purified by reverse phase HPLC(10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)) to giveN—(((S)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-3-yl)methyl)cyclopropanecarboxamideas the TFA salt. LC/MS: m/z 417.5 (M+H)⁺ at 2.30 min (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)).

Example 227 (Pyridin-3-yl)methyl1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-4-ylcarbamate

tert-Butyl1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-4-ylcarbamate

To a suspension of 2-(4-chloro-7-methylquinazolin-2-yl)phenol (2.0 g,7.38 mmol) in CH₂Cl₂ (25 ml) at 0° C. under an N₂ atmosphere was addeddropwise a solution of tert-butyl piperidin-4-ylcarbamate (1.92 g, 9.6mmol) in CH₂Cl₂ (10 ml) and triethylamine (2.0 ml, 14.76 mmol). Thereaction was stirred for 6 hours, then it was quenched with water (25ml), and the layers were separated. The aqueous phase was extractedtwice with CH₂Cl₂ (10 ml), and the combined organic layers were driedover MgSO₄, filtered, and concentrated to give tert-butyl1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-4-ylcarbamateas a yellow solid (3.24 g, 100%). LC/MS: m/z 435.3 (M+H)⁺ at 2.79 min(10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)).

2-(4-(4-Aminopiperidin-1-yl)-7-methylquinazolin-2-yl)phenol

tert-Butyl1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-4-ylcarbamate(3.21 g, 7.39 mmol) was dissolved in CH₂Cl₂ (55 ml). TFA (50 ml) wasadded and the reaction was stirred for 1 hour. After evaporating thesolvents in vacuo, the crude material was diluted with CH₂Cl₂ andneutralized with a 1 N NaOH solution. The layers were separated, and theaqueous layer was extracted three times with CH₂Cl₂ (30 ml). Thecombined organic layers were dried over MgSO₄, filtered, andconcentrated to give2-(4-(4-aminopiperidin-1-yl)-7-methylquinazolin-2-yl)phenol as a yellowsolid (2.06 g, 83%). LC/MS: m/z 335.3 (M+H)⁺ at 1.42 min (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)).

(Pyridin-3-yl)methyl1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-4-ylcarbamate

To a solution of2-(4-(4-aminopiperidin-1-yl)-7-methylquinazolin-2-yl)phenol (50 mg, 0.15mmol) in DMSO (1 mL) was added (pyridin-3-yl)methyl1H-imidazole-1-carboxylate (53 mg, 0.263 mmol) and triethylamine (30.4mg, 42 μL, 0.3 mmol). The reaction was stirred overnight at roomtemperature and then purified by reverse phase HPLC (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)) to give (pyridin-3-yl)methyl1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-4-ylcarbamateas the TFA salt. LC/MS: m/z 470.5 (M+H)⁺ at 1.98 min (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)).

Example 228 (Pyridin-4-yl)methyl1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-4-ylcarbamate

(Pyridin-4-yl)methyl1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-4-ylcarbamate

To a solution of2-(4-(4-aminopiperidin-1-yl)-7-methylquinazolin-2-yl)phenol (50 mg, 0.15mmol) in DMSO (1 mL) was added (pyridin-4-yl)methyl1H-imidazole-1-carboxylate (53 mg, 0.263 mmol) and triethylamine (30.4mg, 42 μL, 0.3 mmol). The reaction was stirred overnight at roomtemperature and purified by reverse phase HPLC (10%-99% CH₃CN (0.035%TFA)/H₂O (0.05% TFA)) to give (pyridin-4-yl)methyl1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-4-ylcarbamateas the TFA salt. LC/MS: m/z 470.5 (M+H)⁺ at 1.98 min (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)).

Example 229 (Benzo[d][1,3]dioxol-7-yl)methyl1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-4-ylcarbamate

(Benzo[d][1,3]dioxol-7-yl)methyl1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-4-ylcarbamate

To a solution of2-(4-(4-aminopiperidin-1-yl)-7-methylquinazolin-2-yl)phenol (50 mg, 0.15mmol) in DMSO (1 mL), was added (benzo[d][1,3]dioxol-4-yl)methyl1H-imidazole-1-carboxylate (65 mg, 0.263 mmol), followed by the additionof triethylamine (30.4 mg, 42 μL, 0.3 mmol). The reaction was stirredovernight at room temperature and then purified by reverse phase HPLC(10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)) to give(benzo[d][1,3]dioxol-7-yl)methyl1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-4-ylcarbamateas the TFA salt. LC/MS: m/z 513.3 (M+H)⁺ at 2.82 min (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)).

Example 230N-((Tetrahydrofuran-2-yl)methyl)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidine-3-carboxamide

N-((Tetrahydrofuran-2-yl)methyl)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidine-3-carboxamide

A solution of1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidine-3-carboxylicacid (45 mg, 0.12 mmol) in 500 μL DMF was cooled to 0° C., and(tetrahydrofuran-2-yl)methanamine (13.2 mg, 0.13 mmol) and triethylamine(25 mg, 35 μL, 0.25 mmol) were added. After ten minutes HATU (57 mg,0.15 mmol) was added to the reaction mixture in one portion. Thereaction was allowed to warm to room temperature, stirred overnight, andpurified by reverse phase HPLC (10%-99% CH₃CN (0.035% TFA)/H₂O (0.05%TFA)) yieldingN-((tetrahydrofuran-2-yl)methyl)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidine-3-carboxamideas the TFA salt. LC/MS: m/z 447.3 (M+H)⁺ at 2.21 min (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)).

Example 231 (S)-Tetrahydrofuran-3-yl((S)-1-(2-(2-fluoro-6-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-3-yl)methylcarbamate

tert-butyl piperidin-3-ylmethylcarbamate

A cold solution of HCl in MeOH (prepared by adding acetyl chloride (13.5mL, 14.9 g, 0.19 mol) to 1 L of MeOH) was added to a cold solution oftert-butyl pyridin-3-ylmethylcarbamate (41.0 grams, 0.20 mol) in MeOH(100 mL). The solution was transferred to a Parr hydrogenation apparatusat 12° C. PtO₂ (3 g) was added, and 12 bar pressure of H₂ was applied.After 16 hours ¹H NMR of a concentrated sample indicated the reaction tobe complete. The catalyst was filtered, and conc. aq. NaOH (20 mL) wasadded to neutralize the HCl. The solution was concentrated to remove thebulk of the MeOH and extracted with tert-butyl methyl ether (4×200 mL).The combined organic layers were washed with saturated aqueous NaClsolution, dried over Na₂SO₄, and concentrated to give the product (40.16g, 0.187 mol, 95%) as a yellow oil that crystallized upon standing. ¹HNMR (300 MHz, CDCl₃): δ 4.62 (bs. s, 1H), 3.06-2.94 (m, 4H), 2.52 (dt,J=12 Hz, 3 Hz, 1H), 2.28 (dd, J=12 Hz, 10 Hz, 1H), 1.82-1.72 (m, 1H),1.70-1.51 (m, 3H), 1.49-1.34 (m, 1H), 1.42 (s, 9H), 1.06 (dq, J=12 Hz, 4Hz, 1H) ppm.

(R)-tert-Butyl piperidin-3-ylmethylcarbamate

To a solution of tert-butyl piperidin-3-ylmethylcarbamate (162 g, 0.758mol) in EtOH was added (+)-dianisoyltartaric acid (316 g, 0.756 mol).The suspension was heated until clear and allowed to cool to roomtemperature overnight. The precipitated salt was recrystallized threetimes from EtOH. The salt was washed with EtOH (2×200 mL) and air-dried.Residual solvent was removed in vacuo. The salt was taken up intert-butyl methyl ether and 10% aq. NaOH. The organic layer wasseparated, and the aqueous layer was extracted with tert-butyl methylether (3×200 mL). More product was extracted after addition of 30% aq.NaOH to the aqueous layer. The combined organic layers were washed withwater and saturated aqueous NaCl solution, dried over Na₂SO₄, andconcentrated to give (R)-tert-butyl piperidin-3-ylmethylcarbamate as awhite crystalline solid (41.3 g, 0.192 mol, 25%). For ee determinations,samples of the salt were taken up in CH₂Cl₂ and 1 N aq. NaOH. Theorganic layer was washed with water, dried over Na₂SO₄, and filtered. Adrop of 1-naphthyl isocyanate was added, and after 15 minutes a drop ofmorpholine was added to quench excess isocyanate. Volatiles wereevaporated after another 15 minutes. The sample was dissolved in EtOHfor chiral HPLC (Chiralcel OD-H; heptane/EtOH/Et₂NH 90/10/0.2; 0.5mL/min; Rt (R): 46 min, Rt (S): 57 min, Rt(N-(naphthalen-1-yl)morpholine-4-carboxamide): 64 min.

2-(4-((S)-3-(Aminomethyl)piperidin-1-yl)-7-methylquinazolin-2-yl)-3-fluorophenol

2-(4-Chloro-7-methylquinazolin-2-yl)-3-fluorophenol (1.0 g, 3.46 mmol)was dissolved in 15 mL anhydrous CH₂Cl₂ under an N₂ atmosphere andcooled using an ice bath and (S)-piperidin-3-ylmethyl-carbamic acidtert-butyl ester/oxalic acid (1.16 g, 3.81 mmol) was added in portions,followed by triethylamine (1.05 g, 1.45 mL, 10.4 mmol). The reaction wasallowed to warm to room temperature and was complete after 1.5 hour. Themixture was partitioned between CH₂Cl₂ and H₂O and separated, and theaqueous layer was extracted once more with CH₂Cl₂. The organic extractswere combined, dried over Na₂SO₄, filtered, and concentrated to a yellowsolid. This solid was suspended in 40 mL CH₂Cl₂ and 20 mL of TFA wereadded. The reaction was complete after 1 hour. The solvent and theexcess TFA were removed in vacuo, the residue was re-dissolved inCH₂Cl₂, and the pH was adjusted to 7 using an aqueous 1 M solution ofNaOH. The reaction was partitioned between CH₂Cl₂ and H₂O and separated,and the aqueous layer was extracted once more with CH₂Cl₂. The organicextracts were combined, dried over Na₂SO₄, filtered, and concentrated toyield of 2-(4-((S)-3-(aminomethyl)piperidin-1-yl)-7-methylquinazolin-2-yl)-3-fluorophenol (900 mg, 71%overall yield) as a yellow solid. LC/MS: m/z 367.3 (M+H)⁺ at 1.35 min(10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)).

(S)-Tetrahydrofuran-3-yl((S)-1-(2-(2-fluoro-6-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-3-yl)methylcarbamate

2-(4-((S)-3-(Aminomethyl)piperidin-1-yl)-7-methylquinazolin-2-yl)-3-fluorophenol(40 mg, 0.11 mmol) was dissolved in anhydrous DMF (800 μL) and cooled to0° C., upon which (S)-tetrahydrofuran-3-yl chloroformate (16.3 mg, 0.12mmol) dissolved in DMF (100 μL) was added dropwise followed bytriethylamine (22 mg, 30.3 μL, 0.218 mmol). The reaction was allowed towarm to room temperature, and after 2 h the reaction was complete. Themixture was purified using reverse phase HPLC (10%-99% CH₃CN (0.035%TFA)/H₂O (0.05% TFA)) to yield (S)-tetrahydrofuran-3-yl((S)-1-(2-(2-fluoro-6-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-3-yl)methylcarbamateas the TFA salt. LC/MS: m/z 481.1 (M+H)⁺ at 2.17 min (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)).

Example 232(2R)-2-Hydroxy-N-(1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-4-yl)-4,4-dimethylpentanamide

(2R)-2-Hydroxy-N-(1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-4-yl)-4,4-dimethylpentanamide

2-(4-(4-Aminopiperidin-1-yl)-7-methylquinazolin-2-yl)phenol (50 mg, 0.15mmol) was dissolved in DMF (1 mL) and cooled to 0° C.(2R)-Hydroxy-4,4-dimethyl-pentanoic acid (26.3 mg, 0.18 mmol) was addedfollowed by the addition of triethylamine (42 μL, 0.3 mmol). After tenminutes, HATU (68 mg, 0.18 mmol) was added in one portion. The reactionwas stirred at 0° C. for 10 minutes, and then allowed to warm to roomtemperature. The reaction was complete after 40 minutes, then filtered,and purified by reverse phase HPLC (10%-99% CH₃CN (0.035% TFA)/H₂O(0.05% TFA)) to give(2R)-2-hydroxy-N-(1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-4-yl)-4,4-dimethylpentanamideas the TFA salt. LC/MS: m/z 463.3 (M+H)⁺ at 2.58 min (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)).

Example 2332-Hydroxy-N-(1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-4-yl)-2-methylpropanamide

2-Hydroxy-N-(1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-4-yl)-2-methylpropanamide

To 2-hydroxy-2-methylpropanoic acid (28 mg, 0.27 mmol) was added asolution of 2-(4-(4-aminopiperidin-1-yl)-7-methylquinazolin-2-yl)phenol(0.07 g, 0.21 mmol) in DMF (0.5 mL), followed by the addition oftriethylamine (0.058 mL, 0.42 mmol) and a solution of HATU (0.103 g,0.273 mmol) in DMF (0.5 mL). The reaction was stirred overnight,filtered, and purified using reverse phase HPLC (10%-99% CH₃CN (0.035%TFA)/H₂O (0.05% TFA)) to afford2-hydroxy-N-(1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-4-yl)-2-methylpropanamideas the TFA salt. LC/MS: m/z 421.2 (M+H)⁺ at 2.17 min (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)).

Example 2342-Ethyl-2-hydroxy-N-(1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-4-yl)butanamide

2-Ethyl-2-hydroxy-N-(1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-4-yl)butanamide

To 2-ethyl-2-hydroxybutanoic acid (36 mg, 0.27 mmol) was added asolution of 2-(4-(4-aminopiperidin-1-yl)-7-methylquinazolin-2-yl)phenol(0.07 g, 0.21 mmol) in DMF (0.5 mL) followed by the addition oftriethylamine (0.058 mL, 0.42 mmol) and a solution HATU (0.103 g, 0.273mmol) in DMF (0.5 mL). The reaction was stirred overnight, filtered, andpurified using reverse phase HPLC (10%-99% CH₃CN (0.035% TFA)/H₂O (0.05%TFA)) to afford2-ethyl-2-hydroxy-N-(1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-4-yl)butanamideas the TFA salt. LC/MS: m/z 449.2 (M+H)⁺ at 2.42 min (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)).

Example 2352-Hydroxy-N-(1-(2-(2-hydroxyphenyl)quinazolin-4-yl)piperidin-4-yl)-2-methylpropanamide

tert-Butyl 1-(2-(2-hydroxyphenyl)quinazolin-4-yl)piperidin-4-ylcarbamate

To a suspension of 2-(4-chloroquinazolin-2-yl)phenol (2.0 g, 7.79 mmol)in CH₂Cl₂ (25 mL) at 0° C. under an N₂ atmosphere, was added dropwisetert-butyl piperidin-4-ylcarbamate (2.08 g, 10.13 mmol) andtriethylamine (2.20 mL, 15.8 mmol) in CH₂Cl₂ (10 mL). The reaction wasstirred overnight, quenched with water and extracted with CH₂Cl₂, andthe combined organic layers were dried over MgSO₄, filtered, andconcentrated to afford tert-butyl1-(2-(2-hydroxyphenyl)quinazolin-4-yl)piperidin-4-ylcarbamate (3.27 g,100%-solvent residue). LC/MS: m/z 421.3 (M+H)⁺ at 2.70 min (10%-99%CH₃CN (0.035% TFA)/H₂O (0.05% TFA)).

2-(4-(4-Aminopiperidin-1-yl)quinazolin-2-yl)phenol

To a solution of tert-butyl1-(2-(2-hydroxyphenyl)quinazolin-4-yl)piperidin-4-ylcarbamate (3.27 g,8.09 mmol) in CH₂Cl₂ (75 mL) was added TFA (50 mL). The reaction wascomplete after 45 minutes After evaporating the solvents in vacuo, thecrude material was diluted with CH₂Cl₂ and neutralized by adding a 1 Naqueous NaOH solution. The layers were separated, and the aqueous layerwas extracted with CH₂Cl₂ (2×15 mL). The combined organic layers weredried over MgSO₄, filtered, and concentrated to afford2-(4-(4-aminopiperidin-1-yl)quinazolin-2-yl)phenol as a solid (2.09 g,84%). LC/MS: m/z 321.3 (M+H)⁺ at 1.28 min (10%-99% CH₃CN (0.035%TFA)/H₂O (0.05% TFA)).

2-Hydroxy-N-(1-(2-(2-hydroxyphenyl)quinazolin-4-yl)piperidin-4-yl)-2-methylpropanamide

To 2-hydroxy-2-methylpropanoic acid (27 mg, 0.28 mmol) was added asolution of 2-(4-(4-aminopiperidin-1-yl)quinazolin-2-yl)phenol (0.07 g,0.22 mmol) in DMF (0.5 mL) followed by the addition of triethylamine(0.061 mL, 0.44 mmol) and a solution of HATU (0.107 g, 0.284 mmol) inDMF (0.5 mL). The reaction was stirred overnight, filtered, and purifiedusing reverse phase HPLC (10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)) toafford2-hydroxy-N-(1-(2-(2-hydroxyphenyl)quinazolin-4-yl)piperidin-4-yl)-2-methylpropanamideas the TFA salt. LC/MS: m/z 407.5 (M+H)⁺ at 2.04 min (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)).

Example 236(2R)-2-Hydroxy-N-(1-(2-(2-hydroxyphenyl)quinazolin-4-yl)piperidin-4-yl)butanamide

(2R)-2-Hydroxy-N-(1-(2-(2-hydroxyphenyl)quinazolin-4-yl)piperidin-4-yl)butanamide

To (R)-2-hydroxybutanoic acid (30 mg, 0.28 mmol) was added a solution of2-(4-(4-aminopiperidin-1-yl)quinazolin-2-yl)phenol (0.07 g, 0.22 mmol)in DMF (0.5 mL) followed by the addition of triethylamine (0.061 mL,0.44 mmol) and a solution of HATU (0.107 g, 0.284 mmol) dissolved in DMF(0.5 mL). The reaction was stirred overnight, filtered, and purifiedusing reverse phase HPLC (10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)) toafford(2R)-2-hydroxy-N-(1-(2-(2-hydroxyphenyl)quinazolin-4-yl)piperidin-4-yl)butanamideas the TFA salt. LC/MS: m/z 407.3 (M+H)⁺ at 2.08 min (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)).

Example 237(2S)-2-Hydroxy-N-(1-(2-(2-hydroxyphenyl)quinazolin-4-yl)piperidin-4-yl)butanamide

(2S)-2-Hydroxy-N-(1-(2-(2-hydroxyphenyl)quinazolin-4-yl)piperidin-4-yl)butanamide

To (S)-2-hydroxybutanoic acid (30 mg, 0.28 mmol) was added a solution of2-(4-(4-aminopiperidin-1-yl)quinazolin-2-yl)phenol (0.07 g, 0.22 mmol)in DMF (0.5 mL) followed by the addition of triethylamine (0.061 mL,0.44 mmol) and a solution of HATU (0.107 g, 0.284 mmol) in DMF (0.5 mL).The reaction was stirred overnight, filtered, and purified using reversephase HPLC (10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)) to afford(2S)-2-hydroxy-N-(1-(2-(2-hydroxyphenyl)quinazolin-4-yl)piperidin-4-yl)butanamideas the TFA salt. LC/MS: m/z 407.3 (M+H)⁺ at 2.09 min (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)).

Example 2382-Hydroxy-N-(1-(2-(2-hydroxyphenyl)quinazolin-4-yl)piperidin-4-yl)hexanamide

2-Hydroxy-N-(1-(2-(2-hydroxyphenyl)quinazolin-4-yl)piperidin-4-yl)hexanamide

To 2-hydroxyhexanoic acid (38 mg, 0.28 mmol) was added a solution of2-(4-(4-aminopiperidin-1-yl)quinazolin-2-yl)phenol (0.07 g, 0.22 mmol)in DMF (0.5 mL) followed by the addition of triethylamine (0.061 mL,0.44 mmol) and a solution of HATU (0.107 g, 0.284 mmol) in DMF (0.5 mL).The reaction was stirred overnight, filtered, and purified using reversephase HPLC (10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)) to afford2-hydroxy-N-(1-(2-(2-hydroxyphenyl)quinazolin-4-yl)piperidin-4-yl)hexanamideas the TFA salt. LC/MS: m/z 435.3 (M+H)⁺ at 2.4 min (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)).

Example 2392-(Trifluoromethyl)-2-hydroxy-N-(1-(2-(2-hydroxyphenyl)quinazolin-4-yl)piperidin-4-yl)propanamide

2-(Trifluoromethyl)-2-hydroxy-N-(1-(2-(2-hydroxyphenyl)quinazolin-4-yl)piperidin-4-yl)propanamide

To 2-(trifluoromethyl)-2-hydroxypropanoic acid (45 mg, 0.28 mmol) wasadded a solution of 2-(4-(4-aminopiperidin-1-yl)quinazolin-2-yl)phenol(0.07 g, 0.22 mmol) dissolved in DMF (0.5 mL) followed by the additionof triethylamine (0.061 mL, 0.44 mmol) and a solution of HATU (0.107 g,0.284 mmol) in DMF (0.5 mL). The reaction was stirred overnight,filtered, and purified using reverse phase HPLC (10%-99% CH₃CN (0.035%TFA)/H₂O (0.05% TFA)) to afford2-(trifluoromethyl)-2-hydroxy-N-(1-(2-(2-hydroxyphenyl)quinazolin-4-yl)piperidin-4-yl)propanamideas the TFA salt. LC/MS: m/z 461.1 (M+H)⁺ at 2.4 min (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)).

Example 2402-Ethyl-2-hydroxy-N-(1-(2-(2-hydroxyphenyl)quinazolin-4-yl)piperidin-4-yl)butanamide

2-Ethyl-2-hydroxy-N-(1-(2-(2-hydroxyphenyl)quinazolin-4-yl)piperidin-4-yl)butanamide

To 2-ethyl-2-hydroxybutanoic acid (38 mg, 0.28 mmol) was added asolution of 2-(4-(4-aminopiperidin-1-yl)quinazolin-2-yl)phenol (0.07 g,0.22 mmol) in DMF (0.5 mL) followed by the addition of triethylamine(0.061 mL, 0.44 mmol) and a solution of HATU (0.107 g, 0.284 mmol) inDMF (0.5 mL). The reaction was stirred overnight, filtered, and purifiedusing reverse phase HPLC (10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)) toafford2-ethyl-2-hydroxy-N-(1-(2-(2-hydroxyphenyl)quinazolin-4-yl)piperidin-4-yl)butanamideas the TFA salt. LC/MS: m/z 435.5 (M+H)⁺ at 2.29 min (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)).

Example 2412-Hydroxy-N-(1-(2-(2-hydroxyphenyl)quinazolin-4-yl)piperidin-4-yl)pentanamide

2-Hydroxy-N-(1-(z-(2-hydroxyphenyl)quinazolin-4-yl)piperidin-4-yl)pentanamide

To 2-hydroxypentanoic acid (34 mg, 0.28 mmol) was added a solution of2-(4-(4-aminopiperidin-1-yl)quinazolin-2-yl)phenol (0.07 g, 0.22 mmol)in DMF (0.5 mL) followed by the addition of triethylamine (0.061 mL,0.44 mmol) and a solution of HATU (0.107 g, 0.284 mmol) in DMF (0.5 mL).The reaction was stirred overnight, filtered, and purified using reversephase HPLC (10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)) to afford2-hydroxy-N-(1-(2-(2-hydroxyphenyl)quinazolin-4-yl)piperidin-4-yl)pentanamideas the TFA salt. LC/MS: m/z 421.1 (M+H)⁺ at 2.24 min (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)).

Example 2422-Hydroxy-N-(1-(2-(2-hydroxyphenyl)quinazolin-4-yl)piperidin-4-yl)-2-methylbutanamide

2-Hydroxy-N-(1-(2-(2-hydroxyphenyl)quinazolin-4-yl)piperidin-4-yl)-2-methylbutanamide

To 2-hydroxy-2-methylbutanoic acid (34 mg, 0.28 mmol) was added asolution of 2-(4-(4-aminopiperidin-1-yl)quinazolin-2-yl)phenol (0.07 g,0.22 mmol) in DMF (0.5 mL), followed by the addition of triethylamine(0.061 mL, 0.44 mmol) and a solution of HATU (0.107 g, 0.284 mmol) inDMF (0.5 mL). The reaction was stirred overnight, filtered, and purifiedusing reverse phase HPLC (10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)) toafford2-hydroxy-N-(1-(2-(2-hydroxyphenyl)quinazolin-4-yl)piperidin-4-yl)-2-methylbutanamideas the TFA salt. LC/MS: m/z 421.3 (M+H)⁺ at 2.18 min (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)).

Example 243(2R)-2-Hydroxy-N-(1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-4-yl)butanamide

(2R)-2-Hydroxy-N-(1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-4-yl)butanamide

To (R)-2-hydroxybutanoic acid (28 mg, 0.27 mmol) was added a solution of2-(4-(4-aminopiperidin-1-yl)-7-methylquinazolin-2-yl)phenol (0.07 g,0.21 mmol) in DMF (0.5 mL) followed by the addition of triethylamine(0.058 mL, 0.42 mmol) and a solution of HATU (0.103 g, 0.273 mmol) inDMF (0.5 mL). The reaction was stirred overnight, filtered, and purifiedusing reverse phase HPLC (10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)) toafford(2R)-2-hydroxy-N-(1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-4-yl)butanamideas the TFA salt. LC/MS: m/z 421.3 (M+H)⁺ at 2.18 min (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)).

Example 244(2S)-2-Hydroxy-N-(1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-4-yl)butanamide

(2S)-2-Hydroxy-N-(1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-4-yl)butanamide

To (S)-2-hydroxybutanoic acid (28 mg, 0.27 mmol) was added a solution of2-(4-(4-aminopiperidin-1-yl)-7-methylquinazolin-2-yl)phenol (0.07 g,0.21 mmol) in DMF (0.5 mL), followed by the addition of triethylamine(0.058 mL, 0.42 mmol) and a solution of HATU (0.103 g, 0.273 mmol) inDMF (0.5 mL). The reaction was stirred overnight, then filtered, andpurified using reverse phase HPLC (10%-99% CH₃CN (0.035% TFA)/H₂O (0.05%TFA)) to afford(2S)-2-hydroxy-N-(1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-4-yl)butanamideas the TFA salt. LC/MS: m/z 421.3 (M+H)⁺ at 2.18 min (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)).

Example 2452-Hydroxy-N-(1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-4-yl)hexanamide

2-Hydroxy-N-(1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-4-yl)hexanamide

To 2-hydroxyhexanoic acid (36 mg, 0.27 mmol) was added a solution of2-(4-(4-aminopiperidin-1-yl)-7-methylquinazolin-2-yl)phenol (0.07 g,0.21 mmol) in DMF (0.5 mL) followed by the addition of triethylamine(0.058 mL, 0.42 mmol) and a solution of HATU (0.103 g, 0.273 mmol) inDMF (0.5 mL). The reaction was stirred overnight, filtered, and purifiedusing reverse phase HPLC (10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)) toafford2-hydroxy-N-(1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-4-yl)hexanamideas the TFA salt. LC/MS: m/z 449.3 (M+H)⁺ at 2.45 min (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)).

Example 2462-(Trifluoromethyl)-2-hydroxy-N-(1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-4-yl)propanamide

2-(Trifluoromethyl)-2-hydroxy-N-(1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-4-yl)propanamide

To 2-(trifluoromethyl)-2-hydroxypropanoic acid (43 mg, 0.27 mmol) wasadded a solution of2-(4-(4-aminopiperidin-1-yl)-7-methylquinazolin-2-yl)phenol (0.07 g,0.21 mmol) in DMF (0.5 mL) followed by the addition of triethylamine(0.058 mL, 0.42 mmol) and a solution of HATU (0.103 g, 0.273 mmol) inDMF (0.5 mL). The reaction was stirred overnight, filtered, and purifiedusing reverse phase HPLC (10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)) toafford2-(trifluoromethyl)-2-hydroxy-N-(1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-4-yl)propanamideas the TFA salt. LC/MS: m/z 475.1 (M+H)⁺ at 2.46 min (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)).

Example 2472-Hydroxy-N-(1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-4-yl)pentanamide

2-Hydroxy-N-(1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-4-yl)pentanamide

To 2-hydroxypentanoic acid (32 mg, 0.27 mmol) was added a solution of2-(4-(4-aminopiperidin-1-yl)-7-methylquinazolin-2-yl)phenol (0.07 g,0.21 mmol) in DMF (0.5 mL), followed by the addition of triethylamine(0.058 mL, 0.42 mmol) and a solution of HATU (0.103 g, 0.273 mmol) inDMF (0.5 mL). The reaction was stirred overnight, filtered, and purifiedusing reverse phase HPLC (10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)) toafford2-hydroxy-N-(1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-4-yl)pentanamideas the TFA salt. LC/MS: m/z 435.3 (M+H)⁺ at 2.31 min (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)).

Example 2482-Hydroxy-N-(1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-4-yl)-2-methylbutanamide

2-Hydroxy-N-(1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-4-yl)-2-methylbutanamide

To 2-hydroxy-2-methylbutanoic acid (32 mg, 0.27 mmol) was added asolution of 2-(4-(4-aminopiperidin-1-yl)-7-methylquinazolin-2-yl)phenol(0.07 g, 0.21 mmol) in DMF (0.5 mL) followed by the addition oftriethylamine (0.058 mL, 0.42 mmol) and a solution of HATU (0.103 g,0.273 mmol) in DMF (0.5 mL). The reaction was stirred overnight,filtered, and purified using reverse phase HPLC (10%-99% CH₃CN (0.035%TFA)/H₂O (0.05% TFA)) to afford2-hydroxy-N-(1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-4-yl)-2-methylbutanamideas the TFA salt. LC/MS: m/z 435.3 (M+H)⁺ at 2.24 min (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)).

Example 249(2R)—N-(1-(2-(2-Fluoro-6-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-4-yl)-2-hydroxy-4,4-dimethylpentanamide

tert-Butyl1-(2-(2-fluoro-6-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-4-ylcarbamate

To a solution of 2-(4-chloro-7-methylquinazolin-2-yl)-3-fluorophenol(700 mg, 2.42 mmol) in 10 ml CH₂Cl₂ at 0° C. was added triethylamine(0.67 mL, 4.8 mmol) followed by the addition of tert-butylpiperidin-4-ylcarbamate (630 mg, 3.14 mmol) under an N₂ atmosphere. Thereaction was gradually warmed to room temperature and stirred overnight.The reaction mixture was then quenched with water, and the layers wereseparated. The aqueous layer was extracted twice with CH₂Cl₂, and thecombined organic layers were dried over MgSO₄, filtered, andconcentrated to obtain tert-butyl1-(2-(2-fluoro-6-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-4-ylcarbamate(1.05 g, 96%) LC/MS: m/z 453.3 (M+H)⁺ at 2.60 min (10%-99% CH₃CN (0.035%TFA)/H₂O (0.05% TFA)).

2-(4-(4-Aminopiperidin-1-yl)-7-methylquinazolin-2-yl)-3-fluorophenol

To a solution of tert-butyl1-(2-(2-fluoro-6-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-4-ylcarbamate(1.05 g, 2.3 mmol) in 20 ml CH₂Cl₂ was slowly added TFA (5 mL). Thereaction was stirred for one hour before it was evaporated to dryness.To the residue was added CH₂Cl₂, and the reaction was neutralized usingan aqueous 1 M NaOH solution. The aqueous layer was extracted twice withCH₂Cl₂, and the combined organic layers were dried over MgSO4, filtered,and concentrated to obtain2-(4-(4-aminopiperidin-1-yl)-7-methylquinazolin-2-yl)-3-fluorophenol(0.75 g, 92%). LC/MS: m/z 353.3 (M+H)⁺ at 1.35 min (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)).

(2R)—N-(1-(2-(2-Fluoro-6-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-4-yl)-2-hydroxy-4,4-dimethylpentanamide

To a solution of2-(4-(4-aminopiperidin-1-yl)-7-methylquinazolin-2-yl)-3-fluorophenol (50mg, 0.14 mmol) in 1 mL DMF at 0° C. was added(R)-2-hydroxy-4,4-dimethylpentanoic acid (25 mg, 0.17 mmol), followed bythe addition of triethylamine (29 mg, 0.28 mmol). HATU (65 mg, 0.17mmol) was then added, and the reaction was stirred at 0° C. for anadditional 10 minutes and then warmed to room temperature. The reactionwas complete after 40 minutes, filtered, and purified by reverse phaseHPLC (10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)) to give(2R)—N-(1-(2-(2-fluoro-6-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-4-yl)-2-hydroxy-4,4-dimethylpentanamideas the TFA salt. LC/MS: m/z 481.3 (M+H)⁺ at 2.42 min (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)).

Example 250 Isobutyl(1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-3-yl)methylcarbamate

Isobutyl(1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-3-yl)methylcarbamate

2-(4-(3-(Aminomethyl)piperidin-1-yl)-7-methylquinazolin-2-yl)phenol (60mg, 0.17 mmol) was dissolved in anhydrous DMF (1 mL) and cooled to 0°C., upon which isobutyl chloroformate (27 μL, 0.2 mmol) dissolved in DMF(100 L) was added dropwise followed by triethylamine (35 mg, 48 μL, 0.34mmol). The reaction was allowed to warm to room temperature, and wascomplete after 2 h. Purification by reverse phase HPLC (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)) gave isobutyl(1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-3-yl)methylcarbamateas the TFA salt. LC/MS: m/z 449.5 (M+H)⁺ at 2.77 min (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)).

Example 251 Ethyl(1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-3-yl)methylcarbamate

Ethyl(1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-3-yl)methylcarbamate

2-(4-(3-(Aminomethyl)piperidin-1-yl)-7-methylquinazolin-2-yl)phenol (60mg, 0.17 mmol) was dissolved in anhydrous DMF (1 mL) and cooled to 0°C., upon which ethyl chloroformate (20 μL, 0.2 mmol) dissolved in DMF(100 μL) was added dropwise followed by the addition of triethylamine(35 mg, 48 μL, 0.34 mmol). The reaction was allowed to warm to roomtemperature and was complete after 2 h. Purification by reverse phaseHPLC (10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)) gave ethyl(1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-3-yl)methylcarbamateas the TFA salt. LC/MS: m/z 421.0 (M+H)⁺ at 2.48 min (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)).

Example 252 Isobutyl((S)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-3-yl)methylcarbamate

Isobutyl((S)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-3-yl)methylcarbamate

2-(4-((S)-3-(Aminomethyl)piperidin-1-yl)-7-methylquinazolin-2-yl)phenol(60 mg, 0.17 mmol) was dissolved in anhydrous DMF (1 mL) and cooled to0° C., upon which isobutyl chloroformate (27 μL, 0.2 mmol) dissolved inDMF (100 μL) was added dropwise followed by the addition oftriethylamine (35 mg, 48 μL, 0.34 mmol). The reaction was allowed towarm to room temperature and was complete after 2 h. Purification byreverse phase HPLC (10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)) gaveisobutyl((S)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-3-yl)methylcarbamateas the TFA salt. LC/MS: m/z 449.3 (M+H)⁺ at 2.80 min (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)).

Example 253 Isobutyl((R)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-3-yl)methylcarbamate

Isobutyl((R)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-3-yl)methylcarbamate

2-(4-((R)-3-(Aminomethyl)piperidin-1-yl)-7-methylquinazolin-2-yl)phenol(60 mg, 0.172 mmol) was dissolved in anhydrous DMF (1 mL) and cooled to0° C., upon which isobutyl chloroformate (27 μL, 0.21 mmol) dissolved inDMF (100 μL) was added dropwise followed by the addition oftriethylamine (35 mg, 48 μL, 0.34 mmol). The reaction was allowed towarm to room temperature, and it was complete after 2 h. Purification byreverse phase HPLC (10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)) gaveisobutyl((R)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-3-yl)methylcarbamateas the TFA salt. LC/MS: m/z 449.3 (M+H)⁺ at 2.78 min (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)).

Example 254Ethyl((S)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-3-yl)methylcarbamate

Ethyl((S)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-3-yl)methylcarbamate

2-(4-((S)-3-(Aminomethyl)piperidin-1-yl)-7-methylquinazolin-2-yl)phenol(35 mg, 0.10 mmol) was dissolved in anhydrous DMF (1 mL) and cooled to0° C., upon which ethyl chloroformate (10.5 μL, 0.11 mmol) dissolved inDMF (100 μL) was added dropwise followed by triethylamine (20.2 mg, 27.8μL, 0.2 mmol). The reaction was allowed to warm to room temperature, andit was complete after 2 h. Purification by reverse phase HPLC (10%-99%CH₃CN (0.035% TFA)/H₂O (0.05% TFA)) gave ethyl((S)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-3-yl)methylcarbamateas the TFA salt. LC/MS: m/z 421.1 (M+H)⁺ at 2.50 min (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)).

Example 255 Isopropyl((S)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-3-yl)methylcarbamate

Isopropyl((S)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-3-yl)methylcarbamate

2-(4-((S)-3-(Aminomethyl)piperidin-1-yl)-7-methylquinazolin-2-yl)phenol(35 mg, 0.10 mmol) was dissolved in anhydrous DMF (1 mL) and cooled to0° C., upon which isopropyl chloroformate (1 M solution in toluene, 98.1mg, 110 μL, 0.11 mmol) was dissolved in DMF (100 μL) and added dropwise,followed by triethylamine (20.2 mg, 27.8 μL, 0.2 mmol). The reaction wasallowed to warm to room temperature, and it was complete after 2 h.Purification by reverse phase HPLC (10%-99% CH₃CN (0.035% TFA)/H₂O(0.05% TFA)) gave isopropyl((S)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-3-yl)methylcarbamateas the TFA salt. LC/MS: m/z 435.5 (M+H)⁺ at 2.61 min (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)).

Example 256 Propyl((S)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-3-yl)methylcarbamate

Propyl((S)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-3-yl)methylcarbamate

2-(4-((S)-3-(Aminomethyl)piperidin-1-yl)-7-methylquinazolin-2-yl)phenol(35 mg, 0.10 mmol) was dissolved in anhydrous DMF (1 mL) and cooled to0° C., upon which propyl chloroformate (12.4 μL, 0.11 mmol) dissolved inDMF (100 μL) was added dropwise followed by triethylamine (20.2 mg, 27.8μL, 0.2 mmol). The reaction was allowed to warm to room temperature andwas complete after 2 h. Purification by reverse phase HPLC (10%-99%CH₃CN (0.035% TFA)/H₂O (0.05% TFA)) gave propyl((S)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-3-yl)methylcarbamateas the TFA salt. LC/MS: m/z 435.5 (M+H)⁺ at 2.61 min (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)).

Example 257 2-Methoxyethyl((S)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-3-yl)methylcarbamate

2-Methoxyethyl-((S)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-3-yl)methylcarbamate

2-(4-((S)-3-(Aminomethyl)piperidin-1-yl)-7-methylquinazolin-2-yl)phenol(35 mg, 0.1 mmol) was dissolved in anhydrous DMF (1 mL) and cooled to 0°C., upon which 2-methoxyethyl chloroformate (11.6 μL, 0.1 mmol)dissolved in DMF (100 μL) was added dropwise followed by triethylamine(20.2 mg, 27.8 μL, 0.2 mmol). The reaction was allowed to warm to roomtemperature, and was complete after 2 h. Purification by reverse phaseHPLC (10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)) gave 2-methoxyethyl((S)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-3-yl)methylcarbamateas the TFA salt. LC/MS: m/z 451.1 (M+H)⁺ at 2.34 min (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)).

Example 258 2-Methoxyethyl1-(6-fluoro-2-(2-hydroxyphenyl)quinazolin-4-yl)piperidin-4-ylcarbamate

2-(4-(4-Aminopiperidin-1-yl)-6-fluoroquinazolin-2-yl)phenol

To a stirred solution of 2-(4-chloro-6-fluoroquinazolin-2-yl)phenol(0.20 g, 0.73 mmol) in CH₂Cl₂ (5 mL) was added dropwise a solution oftert-butyl piperidin-4-ylcarbamate (0.19 g, 0.95 mmol) and triethylamine(203 μL, 147 mg, 1.46 mmol) in CH₂Cl₂. The reaction was stirred for 3 hand then quenched with water. The aqueous layer was extracted withCH₂Cl₂. The combined organic layers were dried over MgSO₄, filtered, andconcentrated to obtain tert-butyl1-(6-fluoro-2-(2-hydroxyphenyl)quinazolin-4-yl)piperidin-4-ylcarbamate.The residue was dissolved in 10 mL CH₂Cl₂ and 3 mL TFA. The reaction wasstirred for 2 hours and neutralized with a 1.0 M aqueous NaOH solution.The mixture was partitioned between H₂O/CH₂Cl₂ and separated, and theaqueous layer was extracted with CH₂Cl₂. The combined organic layerswere dried over MgSO₄, filtered, and concentrated to obtain2-(4-(4-aminopiperidin-1-yl)-6-fluoroquinazolin-2-yl)phenol. LC/MS: m/z339.3 (M+H)⁺ at 1.87 min (10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)).

2-Methoxyethyl1-(6-fluoro-2-(2-hydroxyphenyl)quinazolin-4-yl)piperidin-4-ylcarbamate

A solution of2-(4-(4-aminopiperidin-1-yl)-6-fluoroquinazolin-2-yl)phenol (50 mg, 0.15mmol) in DMF (1 mL) was cooled to −40° C. (external temp). To it wasadded triethylamine (41 μL, 30 mg, 0.29 mmol) and a solution of2-methoxyethyl chloroformate (17 μL, 20 mg, 0.15 mmol) in 100 μL DMFdropwise. The reaction was allowed to warm to room temperature and wasstirred for 2 h. Purification via reverse phase HPLC (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)) gave 2-methoxyethyl1-(6-fluoro-2-(2-hydroxyphenyl)quinazolin-4-yl)piperidin-4-ylcarbamateas the TFA salt. LC/MS: m/z 441.5 (M+H)⁺ at 2.6 min (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)).

Example 259{1-[2-(2-Hydroxy-phenyl)-7-methyl-quinazolin-4-yl]-piperidin-4-yl}-carbamicacid tert-butyl ester

{1-[2-(2-Hydroxy-phenyl)-7-methyl-quinazolin-4-yl]-piperidin-4-yl}-carbamicacid tert-butyl ester

To piperidin-4-yl-carbamic acid tert-butyl ester (887 mg, 4.4 mmol) in10 mL of was CH₂Cl₂ was added sequentially triethylamine (720 μL, 5.2mmol) and 2-(4-chloro-7-methyl-quinazolin-2-yl)-phenol (1.0 g, 3.7mmol). The reaction mixture was stirred at room temperature for 2 h andthen diluted with water and CH₂Cl₂. The organic layer was separated anddried over Na₂SO₄, and the solvent was removed under reduced pressure.The residue was subjected to purification via reverse phase HPLC(10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)) to give{1-[2-(2-hydroxy-phenyl)-7-methyl-quinazolin-4-yl]-piperidin-4-yl}-carbamicacid tert-butyl ester as the TFA salt. LC/MS: m/z 435.2 (M+H)⁺ at 3.03min (10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)).

Example 260 Isobutyl((S)-1-(2-(2-fluoro-6-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-3-yl)methylcarbamate

Isobutyl((S)-1-(2-(2-fluoro-6-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-3-yl)methylcarbamate

To a solution of2-(4-((S)-3-(aminomethyl)piperidin-1-yl)-7-methylquinazolin-2-yl)-3-fluorophenol(40 mg, 0.11 mmol) in DMF (400 μL) at 0° C. was added dropwise isobutylchloroformate (15.7 μL, 0.12 mmol) in DMF (400 μL), followed by theaddition of triethylamine (30 mL, 0.22 mmol). The reaction was allowedto warm to room temperature and was complete after 2 h. Purification byreverse phase HPLC (10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)) gaveisobutyl((S)-1-(2-(2-fluoro-6-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-3-yl)methylcarbamateas the TFA salt. LC/MS: m/z 467.1 (M+H)⁺ at 2.56 min (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)).

Example 261 2-Methoxyethyl((S)-1-(2-(2-fluoro-6-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-3-yl)methylcarbamate

Method A

2-Methoxyethyl((S)-1-(2-(2-fluoro-6-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-3-yl)methylcarbamate

To a solution of2-(4-((S)-3-(aminomethyl)piperidin-1-yl)-7-methylquinazolin-2-yl)-3-fluorophenol(40 mg, 0.11 mmol) in DMF (400 mL) at 0° C. was added dropwise2-methoxyethyl chloroformate (12.6 mL, 0.11 mmol) in DMF (400 mL),followed by the addition of triethylamine (30 mL, 0.22 mmol). Thereaction was allowed to warm to room temperature and was complete after2 h. Purification by reverse phase HPLC (10%-99% CH₃CN (0.035% TFA)/H₂O(0.05% TFA)) gave 2-methoxyethyl((S)-1-(2-(2-fluoro-6-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-3-yl)methylcarbamateas the TFA salt. LC/MS: m/z 469.1 (M+H)⁺ at 2.20 min (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)).

Method B

2-Methoxyethyl((S)-1-(tert-butoxycarbonyl)piperidin-3-yl)methylcarbamate

To a solution of (S)-tert-butyl 3-(aminomethyl)piperidine-1-carboxylate(500 mg, 2.33 mmol) in CH₂Cl₂ at −10° C. was added triethylamine (650μL, 4.66 mmol) followed by the dropwise addition of 2-methoxyethylchloroformate (325 μL, 2.79 mmol). The reaction was warmed to roomtemperature and quenched with water. The aqueous layer was extractedwith CH₂Cl₂, and the combined extracts were dried over MgSO₄, filtered,and evaporated. Purification via silica gel chromatography using 0 to10% EtOAc in CH₂Cl₂ afforded 2-methoxyethyl((S)-1-(tert-butoxycarbonyl)piperidin-3-yl)methylcarbamate (496 mg,67%). LC/MS: m/z 317.3 (M+H)⁺ at 2.56 min (10%-99% CH₃CN (0.035%TFA)/H₂O (0.05% TFA)).

2-Methoxyethyl ((R)-piperidin-3-yl)methylcarbamate

To 2-methoxyethyl((S)-1-(tert-butoxycarbonyl)piperidin-3-yl)methylcarbamate (496 mg, 1.6mmol) dissolved in 10 mL CH₂Cl₂ was added 5 mL TFA, and the reaction wasstirred for 1 hour. After neutralizing the mixture with a 1 N NaOHsolution it was extracted with CH₂Cl₂, and the combined organic layerswere dried over MgSO₄, filtered, and concentrated to give 2-methoxyethyl((R)-piperidin-3-yl)methylcarbamate (300 mg, 87%) which was used withoutfurther purification. LC/MS: m/z 217.5 (M+H)⁺ at 0.49 min (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)).

2-Methoxyethyl((S)-1-(2-(2-fluoro-6-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-3-yl)methylcarbamate

To a solution of 2-methoxyethyl ((R)-piperidin-3-yl)methylcarbamate(0.24 g, 1.1 mmol) and2-(4-chloro-7-methylquinazolin-2-yl)-3-fluorophenol (250 mg, 0.865 mmol)in CH₂Cl₂ was added triethylamine (2.41 mL, 1.73 mmol). After stirringthe reaction at room temperature for 2 h, it was quenched with water andthen extracted with CH₂Cl₂. The combined organic layers were dried overMgSO₄, filtered, and concentrated. Purification via silica gelchromatography using 0%-10% EtOAc in CH₂Cl₂ yielded 2-methoxyethyl((S)-1-(2-(2-fluoro-6-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-3-yl)methylcarbamate(357 mg, 88%). LC/MS: m/z 469.5 (M+H)⁺ at 2.30 min (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)).

2-Methoxyethyl((S)-1-(2-(2-fluoro-6-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-3-yl)methylcarbamatehydrochloride

To a solution of((S)-1-(2-(2-fluoro-6-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-3-yl)methylcarbamate(352 mg, 0.75 mmol) in CH₂Cl₂ (3 mL) was added dropwise a 2.0 M HClsolution in ether (0.375 mL, 0.75 mmol) under an N₂ atmosphere. It wasfollowed by the addition of 20 mL ether which lead to the precipitationof 2-methoxyethyl((S)-1-(2-(2-fluoro-6-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-3-yl)methylcarbamatehydrochloride (350 mg, 92%) which was then filtered and dried. LC/MS:m/z 469.5 (M+H)⁺ at 2.29 min (10%-99% CH₃CN (0.035% TFA)/H₂O (0.05%TFA)). ¹H NMR (400 MHz, DMSO-d6) δ 7.97 (d, J=7.9 Hz, 1H), 7.63 (s, 1H),7.45 (m, 3H), 6.89 (d, J=8.3 Hz, 1H), 6.82 (t, J=9.5 Hz, 1H), 4.54 (s,1H), 4.03 (d, J=2.7 Hz, 2H), 3.47 (t, J=4.6 Hz, 4H), 3.24 (s, 3H), 2.99(m, 2H), 2.54 (s, 3H), 1.89 (m, 3H), 1.70 (m, 1H), 1.38 (m, 1H) ppm.

Example 262 Ethyl((S)-1-(2-(2-fluoro-6-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-3-yl)methylcarbamate

Ethyl((S)-1-(2-(2-fluoro-6-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-3-yl)methylcarbamate

Method A

To a solution of2-(4-((S)-3-(aminomethyl)piperidin-1-yl)-7-methylquinazolin-2-yl)-3-fluorophenol(40 mg, 0.11 mmol) in DMF (400 μL) at 0° C. was added dropwise ethylchloroformate (10.4 μl, 0.10 mmol) in DMF (400 μL), followed by theaddition of triethylamine (30 μL, 0.22 mmol). The reaction was allowedto warm to room temperature and was complete after 2 h. Purification byreverse phase HPLC (10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)) gave2-methoxyethyl ethyl((S)-1-(2-(2-fluoro-6-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-3-yl)methylcarbamateas the TFA salt. LC/MS: m/z 439.5 (M+H)⁺ at 2.31 min (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)).

Method B

To a stirred solution of2-(4-((S)-3-(aminomethyl)piperidin-1-yl)-7-methylquinazolin-2-yl)-3-fluorophenol(200 mg, 0.54 mmol) in 12 mL THF was added diisopropyl ethylamine (188μL, 1.08 mmol) at room temperature. The mixture was cooled to −60° C.,and a solution of ethyl chloroformate (52 μL, 0.54 mmol) in 0.6 mL THFwas added dropwise. After allowing the reaction to warm to roomtemperature, the mixture was partitioned between H₂O and CH₂Cl₂. Thelayers were separated, and the aqueous layer was extracted twice morewith CH₂Cl₂. The organic layers were combined, dried over Na₂SO₄,filtered, and concentrated. Purification via silica gel chromatographyusing 0-10% EtOAc in 50:50 hexanes:CH₂Cl₂ gave ethyl((S)-1-(2-(2-fluoro-6-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-3-yl)methylcarbamate(92 mg, 38%). LC/MS: m/z 439.5 (M+H)⁺ at 2.40 min (10% -99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)).

Ethyl((S)-1-(2-(2-fluoro-6-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-3-yl)methylcarbamatehydrochloride

To a solution of ethyl((S)-1-(2-(2-fluoro-6-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-3-yl)methylcarbamate(89 mg, 0.2 mmol) in 2 mL CH₂Cl₂ under an N₂ atmosphere was added ether(10 mL) followed by the dropwise addition of a 2.0 M solution of HCl inether (0.1 mL, 0.2 mmol) which resulted in precipitation of ethyl((S)-1-(2-(2-fluoro-6-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-3-yl)methylcarbamatehydrochloride which was then filtered and dried (85 mg, 90%). LC/MS: m/z439.5 (M+H)⁺ at 2.37 min (10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)).¹H NMR (400 MHz, DMSO-d6) δ 8.26 (d, J=8.5 Hz, 1H), 7.57 (s, 1H), 7.45(m, 2H), 6.81 (m, 2H), 4.57 (m, 2H), 3.89 (m, 2H), 3.52 (m, 1H), 3.36(m, 1H), 2.95 (s, 2H), 2.52 (s, 3H), 1.86 (m, 3H), 1.66 (m, 1H), 1.39(m, 1H), 1.07 (t, J=6.6 Hz, 3H) ppm.

Example 276 (R)-Tetrahydro-furan-2-carboxylic acid{1-[2-(2-hydroxy-phenyl)-7-methyl-quinazolin-4-yl]-piperidin-4-yl}-amide

(R)-Tetrahydro-furan-2-carboxylic acid{1-[2-(2-hydroxy-phenyl)-7-methyl-quinazolin-4-yl]-piperidin-4-yl}-amide

Method A: (R)-Tetrahydrofuran-2-carboxylic acid (23 mg, 0.20 mmol) andHATU (84 mg, 0.22 mmol) were dissolved in 0.75 mL DMF, thentriethylamine (40 mg, 55 μL, 0.40 mmol) was added, followed immediatelyby 2-[4-(4-Amino-piperidin-1-yl)-7-methyl-quinazolin-2-yl]-phenol (67mg, 0.20 mmol). The reaction was then stirred for 30 min at roomtemperature, diluted with 0.75 mL 1:1 methanol/DMSO, filtered, andpurified by reverse phase HPLC (2-99% CH₃CN (0.035% TFA)/H₂O (0.05%TFA)) to give (R)-Tetrahydro-furan-2-carboxylic acid{1-[2-(2-hydroxy-phenyl)-7-methyl-quinazolin-4-yl]-piperidin-4-yl}-amideas the TFA salt. LC/MS: m/z 433.2 (M+H)⁺ at 2.33 min (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)).

Method B: (R)-Tetrahydrofuran-2-carboxylic acid (193 mg, 1.66 mmol) wasdissolved in DMF (6 mL), followed by the addition of HATU (696 mg, 1.83mmol). The mixture was then stirred for 15 min at room temperature underan N₂ atmosphere. The2-[4-(4-Amino-piperidin-1-yl)-7-methyl-quinazolin-2-yl]-phenol (556 mg,1.66 mmol) was dissolved in DMF (8 mL) and added to the mixture,followed by triethylamine (336 mg, 0.463 mL, 3.32 mmol). After 30 min,theDMF was removed in vacuo and the crude product partitioned betweenwater and ethyl acetate. The aqueous layer was separated, washed withethyl acetate, and the combined organic layers dried over MgSO₄,filtered, and concentrated to give crude product as an orange oil.Purification via silica gel chromatography (20% ethyl acetate/80% 1:1CH₂Cl₂:hexane) gave pure (R)-Tetrahydro-furan-2-carboxylic acid{1-[2-(2-hydroxy-phenyl)-7-methyl-quinazolin-4-yl]-piperidin-4-yl}-amide(303 mg, 42%). ¹H NMR (400 MHz, DMSO-d6) δ 8.44 (dd, J=8.2, 1.5 Hz, 1H),7.90 (d, J=8.5 Hz, 1H), 7.75 (d, J=8.3 Hz, 1H), 7.67 (s, 1H), 7.40-7.36(m, 2H), 6.97-6.93 (m, 2H), 4.48-4.45 (m, 2H), 4.20 (dd, J=8.2, 5.3 Hz,1H), 4.06-3.96 (m, 1H), 3.88 (dd, J=14.3, 6.6 Hz, 1H), 3.74 (dd, J=14.5,6.7 Hz, 1H), 3.43-3.32 (m, 2H), 2.51 (s, 3H), 2.16-2.07 (m, 1H),

(R)-Tetrahydro-furan-2-carboxylic acid{1-[2-(2-hydroxy-phenyl)-7-methyl-quinazolin-4-yl]-piperidin-4-yl}-amidehydrochloride

(R)-Tetrahydro-furan-2-carboxylic acid{1-[2-(2-hydroxy-phenyl)-7-methyl-quinazolin-4-yl]-piperidin-4-yl}-amide(303 mg, 0.701 mmol) was dissolved in 9 mL 2:1 dry ether/dry CH₂Cl₂ and2.0 M HCl in ether added dropwise (0.35 mL, 0.70 mmol), producing awhite precipitate which was collected by filtration to give(R)-Tetrahydro-furan-2-carboxylic acid{1-[2-(2-hydroxy-phenyl)-7-methyl-quinazolin-4-yl]-piperidin-4-yl}-amidehydrochloride (268 mg, 82%). LC/MS: m/z 433.5 (M+H)⁺ at 2.26 min(10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)). ¹H NMR (400 MHz, DMSO-d6)δ 8.20 (dd, J=7.8, 1.2 Hz, 1H), 8.00 (d, J=8.6 Hz, 1H), 7.80-7.79 (m,2H), 7.51-7.47 (m, 2H), 7.15 (d, J=8.2 Hz, 1H), 7.05-7.01 (m, 1H),4.66-4.63 (m, 2H), 4.21 (dd, J=8.2, 5.2 Hz, 1H), 4.12-4.03 (m, 1H),3.91-3.84 (m, 1H), 3.78-3.70 (m, 1H), 3.59 (t, J=12.3 Hz, 2H), 2.54 (s,3H), 2.16-2.05 (m, 1H), 1.97-1.94 (m, 2H), 1.89-1.72 (m, 5H) ppm.

Example 301 (S)-Tetrahydrofuran-3-yl(R)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-ylcarbamate

tert-Butyl(R)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-ylcarbamate

To 2-(4-chloro-7-methyl-quinazolin-2-yl)-phenol (644 mg, 2.4 mmol) in2.9 mL of DMF at room temperature was added sequentially(R)-pyrrolidin-3-yl-carbamic acid tert-butyl ester (857 mg, 4.6 mmol)and triethylamine (662 μL, 4.8 mmol), and the reaction mixture wasstirred for 12 h. The reaction mixture was diluted with water (10 mL)and CH₂Cl₂ (10 mL). The organic layer was separated and dried (Na₂SO₄),and the residue was purified by silica gel chromatography with 25-85%ethyl acetate/hexanes to give tert-butyl(R)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-ylcarbamate(856 mg, 86%). LC/MS: m/z 421 (M+H)⁺ at 2.82 min (10%-99% CH₃CN (0.035%TFA)/H₂O (0.05% TFA)).

(S)-Tetrahydrofuran-3-yl(R)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-ylcarbamate

Method A

To tert-butyl(R)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-ylcarbamate(850 mg, 2.02 mmol) was added at room temperature 4 mL of 1:1TFA:CH₂Cl₂. The reaction mixture was stirred for 50 min, diluted with 20mL of CH₂Cl₂, and washed with 15 mL of satd. NaHCO₃ solution. Theorganic layer was separated and dried over Na₂SO₄, and the solvent wasremoved under reduced pressure to give(R)-2-[4-(3-amino-pyrrolidin-1-yl)-7-methyl-quinazolin-2-yl]-phenol asan oil which was used without further purification.

To 45.9 mg (0.14 mmol) of the amine from above procedure was added 570μL of CH₂Cl₂ and the solution was cooled to 0° C. To this solution wasadded sequentially 24 μL (0.17 mmol) of triethylamine and 19.4 mg (0.13mmol) of (S)-tetrahydro-furan-3-ol chloroformate. The reaction mixturewas stirred at 0° C. for 45 min, diluted with water and CH₂Cl₂ (10 mL).The organic layer was separated and dried over Na₂SO₄, and the solventwas removed under reduced pressure. The residue was purified viapreparative reverse phase HPLC using 10%-99% CH₃CN (0.035% TFA)/H₂O(0.05% TFA) to give (S)-tetrahydrofuran-3-yl(R)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-ylcarbamateas the TFA salt. LC/MS: m/z 435 (M+H)⁺ at 2.41 min (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)).

Method B

To tert-butyl(R)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-ylcarbamate(907.2 mg, 2.16 mmol) was added 4 mL of 1:1 TFA:CH₂Cl₂. The mixture wasstirred at room temperature for 5 hours. The reaction was diluted with asolution of saturated aqueous NaHCO₃ and CH₂Cl₂. The organic layer wasseparated, dried over Na₂SO₄, and concentrated under reduced pressure togive 2-(4-((R)-3-aminopyrrolidin-1-yl)-7-methylquinazolin-2-yl)phenol.To this free amine (640 mg, 2 mmol) was added 8 ml of CH₂Cl₂ andtriethylamine (335 μL, 2.4 mmol). After cooling the mixture to 0° C.,(S)-tetrahydrofuran-3-yl chloroformate (271 mg, 1.8 mmol) was added, andthe reaction was allowed to stir for 30 minutes. Purification on silicagel using 30-100% ethyl acetate/hexanes gave (S)-tetrahydrofuran-3-yl(R)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-ylcarbamate.¹H NMR (400 MHz, CDCl₃) δ 14.8 (bs, 1H), 8.34 (d, J=6.4 Hz, 1H), 7.83(d, J=4.0 Hz, 1H), 7.48 (bs, 1H), 7.27 (m, 1H), 7.08 (d, J=8.1 Hz, 1H),6.93 (d, J=8.1 Hz, 1H), 6.82 (t, J=7.5 Hz, 1H), 5.21 (s, 1H), 5.06 (s,1H), 4.37 (s, 1H), 4.15 (m, 1H), 4.02 (s, 1H), 3.97 (d, J=5.6 Hz, 1H),3.87-3.77 (m, 5H), 2.42 (s, 3H), 2.24 (t, J=6.0 Hz, 1H), 2.15-2.06 (m,1H), 1.98 (q, J=9.3 Hz, 2H) ppm.

(S)-Tetrahydrofuran-3-yl(R)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-ylcarbamatehydrochloride

A 2.0 M HCl solution in Et₂O (192 μL, 0.38 mmol) was slowly added at−20° C. to a stirring solution of (S)-tetrahydrofuran-3-yl(R)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-ylcarbamate(167 mg, 0.38 mmol) in 700 μL of CH₂Cl₂. The reaction was allowed towarm to room temperature and was stirred for 25 minutes. Solvents wereremoved under reduced pressure, and the residue was triturated with Et₂Oand filtered to give (S)-tetrahydrofuran-3-yl(R)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-ylcarbamatehydrochloride. LC/MS: m/z 435.2 (M+H)⁺ at 2.41 min (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)).

Example 302 (R,R)-Tetrahydro-furan-2-carboxylic acid{1-[2-(2-hydroxy-phenyl)-7-methyl-quinazolin-4-yl]-pyrrolidin-3-yl}-amide

(R,R)-Tetrahydro-furan-2-carboxylic acid{1-[2-(2-hydroxy-phenyl)-7-methyl-quinazolin-4-yl]-pyrrolidin-3-yl}-amide

To 850 mg (2.02 mmol) of(R)-{1-[2-(2-hydroxy-phenyl)-7-methyl-quinazolin-4-yl]-pyrrolidin-3-yl}-carbamicacid tert-butyl ester was added at room temperature 4 mL of 1:1TFA:CH₂Cl₂. The reaction mixture was stirred for 50 min and diluted with20 mL of CH₂Cl₂ and extracted with 15 mL of satd. NaHCO₃ solution. Theorganic layer was separated and dried over Na₂SO₄, and the solvent wasremoved under reduced pressure to give(R)-2-[4-(3-amino-pyrrolidin-1-yl)-7-methyl-quinazolin-2-yl]-phenol asan oil which was used without further purification.

To 52.6 mg (0.16 mmol) of the amine from above procedure was added 600μL of CH₂Cl₂. To this solution was added sequentially 27.4 μL (0.19mmol) of triethylamine and 20.9 mg (0.18 mmol) of (R)—tetrahydro-furan-2-carboxylic acid, 24.2 mg (0.18 mmol) of HOBt, 34.6 mg(0.18 mmol) of EDCI at room temperature. The reaction mixture wasstirred for 12 h, then diluted with water and CH₂Cl₂ (10 mL). Theorganic layer was separated and dried over Na₂SO₄, and the solvent wasremoved under reduced pressure. The residue was purified via preparativereverse phase HPLC using 10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA) togive (R,R)-tetrahydro-furan-2-carboxylic acid{1-[2-(2-hydroxy-phenyl)-7-methyl-quinazolin-4-yl]-pyrrolidin-3-yl}-amideas the TFA salt. LC/MS: m/z 419 (M+H)⁺ at 2.35 min (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)).

Example 303(2R)-Tetrahydro-N—((S)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-yl)furan-2-carboxamide

(S)-{1-[2-(2-Hydroxy-phenyl)-7-methyl-quinazolin-4-yl]-pyrrolidin-3-yl}-carbamicacid tert-butyl ester

To 2-(4-chloro-7-methyl-quinazolin-2-yl)-phenol (551 mg, 2.03 mmol) in2.5 mL of DMF at room temperature was added sequentially(S)-pyrrolidin-3-yl-carbamic acid tert-butyl ester (740 mg, 3.9 mmol)and triethylamine (567 μL, 4.0 mmol), and the reaction mixture wasstirred for 12 h. The reaction mixture was diluted with water (10 mL)and CH₂Cl₂ (10 mL). The organic layer was separated and dried (Na₂SO₄),and the residue was purified via silica gel chromatography with 25-85%ethyl acetate/hexanes to give of(S)-{1-[2-(2-hydroxy-phenyl)-7-methyl-quinazolin-4-yl]-pyrrolidin-3-yl}-carbamicacid tert-butyl ester (694 mg, 81%). LC/MS: m/z 421 (M+H)⁺ at 2.79 min(10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)).

(2R)-Tetrahydro-N—((S)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-yl)furan-2-carboxamide

To(S)-{1-[2-(2-hydroxy-phenyl)-7-methyl-quinazolin-4-yl]-pyrrolidin-3-yl}-carbamicacid tert-butyl ester (690 mg, 1.64 mmol) was added at room temperature3 mL of 1:1 TFA:CH₂Cl₂. The reaction mixture was stirred for 55 min,diluted with 20 mL of CH₂Cl₂ and washed with 15 mL of satd. NaHCO₃solution. The organic layer was separated and dried over Na₂SO₄, and thesolvent was removed under reduced pressure to give(S)-2-[4-(3-amino-pyrrolidin-1-yl)-7-methyl-quinazolin-2-yl]-phenol asan oil which was used without further purification.

To the amine from above procedure (133.3 mg, 0.42 mmol) was added 1.6 mLof CH₂Cl₂. To this solution was added sequentially triethylamine (174μL, 1.25 mmol) and (R)-tetrahydro-furan-2-carboxylic acid (57.9 mg, 0.5mmol), HOBt (67.5 mg 0.5 mmol), EDCI (95.8 mg 0.5 mmol) at roomtemperature. The reaction mixture was stirred for 12 h and diluted withwater and CH₂Cl₂ (10 mL). The organic layer was separated and dried overNa₂SO₄, and the solvent was removed under reduced pressure. The residuewas purified via preparative reverse phase HPLC using 10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA) to give(2R)-tetrahydro-N—((S)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-yl)furan-2-carboxamideas the TFA salt. LC/MS: m/z 419 (M+H)⁺ at 2.34 min (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)).

Example 304(S,S)-{1-[2-(2-Hydroxy-phenyl)-7-methyl-quinazolin-4-yl]-pyrrolidin-3-yl}-carbamicacid tetrahydro-furan-3-yl ester

(S,S)-{1-[2-(2-Hydroxy-phenyl)-7-methyl-quinazolin-4-yl]-pyrrolidin-3-yl}-carbamicacid tetrahydro-furan-3-yl ester

To(S)-{1-[2-(2-hydroxy-phenyl)-7-methyl-quinazolin-4-yl]-pyrrolidin-3-yl}-carbamicacid tert-butyl ester (690 mg, 1.64 mmol) was added at room temperature,3 mL of 1:1 TFA:CH₂Cl₂. The reaction mixture was stirred for 55 min,diluted with 20 mL of CH₂Cl₂, and washed with 15 mL of satd. NaHCO₃solution. The organic layer was separated and dried over Na₂SO₄, and thesolvent was removed under reduced pressure to give(S)-2-[4-(3-amino-pyrrolidin-1-yl)-7-methyl-quinazolin-2-yl]-phenol asan oil which was used without further purification.

To the amine from above procedure (134.7 mg, 0.42 mmol) was added 1.6 mLof CH₂Cl₂, and the solution was cooled to 0° C. To this solution wasadded sequentially triethylamine (88 μL, 0.63 mmol) and(S)-tetrahydro-furan-3-ol chloroformate (82.3 mg, 0.55 mmol). Thereaction mixture was stirred and allowed to warm from 0° C. to roomtemperature over 12 h and was diluted with water and CH₂Cl₂ (10 mL). Theorganic layer was separated and dried over Na₂SO₄, and the solvent wasremoved under reduced pressure. The residue was purified via preparativereverse phase HPLC using 10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA) togive(S,S)-{1-[2-(2-hydroxy-phenyl)-7-methyl-quinazolin-4-yl]-pyrrolidin-3-yl}-carbamicacid tetrahydro-furan-3-yl ester as the TFA salt. LC/MS: m/z 435 (M+H)⁺at 2.39 min (10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)).

Example 305 (S)-Tetrahydrofuran-3-yl((S)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-yl)methylcarbamate

Benzyl ((S)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)methylcarbamate

A mixture of (S)-tert-butyl 3-(aminomethyl)pyrrolidine-1-carboxylate(1.0 g, 5.0 mmol) and 50 mL THF was cooled in an ice bath. To this wasadded benzyl chloroformate (0.77 mL, 5.5 mmol), followed bytriethylamine (1.39 mL, 10 mmol). After removing the ice bath, thereaction was stirred for 4 h. The mixture was poured into ice water andextracted with EtOAc. The organic extracts were washed with water, driedover Na₂SO₄, filtered, and concentrated. Purification via silica gelchromatography using EtOAc in hexanes (0-40%) gave benzyl((S)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)methylcarbamate (1.29 g,77%) as a colorless oil. ¹H NMR (400 MHz, CDCl₃) δ 7.39-7.28 (m, 5H),5.10 (s, 2H), 4.87 (s, 1H), 3.52-2.95 (m, 6H), 2.41-2.35 (m, 1H),2.10-1.79 (m, 2H), 1.45 (s, 9H) ppm.

Benzyl((S)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-yl)methylcarbamate

A solution of benzyl((S)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)methylcarbamate (0.20 g,0.60 mmol) and 4 M HCl in dioxane (10 mL) was stirred for 3 h at roomtemperature. After evaporating the solvent under reduced pressure, thesolid was triturated with Et₂O and dried under vacuum, then taken up inCH₂Cl₂ (10 mL). To this solution was added2-(4-chloro-7-methylquinazolin-2-yl)phenol (0.16 g, 0.60 mmol) andtriethylamine (0.25 mL, 1.8 mmol). The reaction mixture was stirred atroom temperature overnight, then diluted with CH₂Cl₂ and washed withwater. The organic extracts were dried over Na₂SO₄, filtered, andconcentrated. Purification via silica gel chromatography using 0-40%EtOAc in hexanes gave benzyl((S)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-yl)methylcarbamateas a colorless oil (0.19 g, 68%). LC/MS: m/z 469.1 (M+H)⁺ at 2.58 min(10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)).

2-(4-((S)-3-(Aminomethyl)pyrrolidin-1-yl)-7-methylquinazolin-2-yl)phenol

A solution of benzyl((S)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-yl)methylcarbamate(0.19 g, 0.41 mmol) and MeOH (5 mL) was stirred with Pd/C (20 mg, 10%weight of Pd on carbon) under an H₂ atmosphere at ambient pressure atambient pressure overnight. Purification via silica gel chromatographyusing MeOH in CH₂Cl₂ (0-10%) gave2-(4-((S)-3-(aminomethyl)pyrrolidin-1-yl)-7-methylquinazolin-2-yl)phenol(27 mg, 19%). LC/MS: m/z 335.5 (M+H)⁺ at 1.28 min (10%-99% CH₃CN (0.035%TFA)/H₂O (0.05% TFA)).

(S)-Tetrahydrofuran-3-yl((S)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-yl)methylcarbamate

A solution of2-(4-((S)-3-(aminomethyl)pyrrolidin-1-yl)-7-methylquinazolin-2-yl)phenol(13 mg, 0.04 mmol) and CH₂Cl₂ (0.5 mL) was cooled in an ice bath. Tothis mixture was added (S)-tetrahydrofuran-3-yl chloroformate (6 μL,0.04 mmol), followed by triethylamine (11 μL, 0.08 mmol). After removingthe ice bath, the reaction was stirred for 3 h at room temperature.Purification via preparative reverse phase HPLC (10%-99% CH₃CN (0.035%TFA)/H₂O (0.05% TFA)) gave (S)-tetrahydrofuran-3-yl((S)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-yl)methylcarbamateas the TFA salt. LC/MS: m/z 449.3 (M+H)⁺ at 2.18 min (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)).

Example 306 (R)-Tetrahydrofuran-3-yl((R)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-yl)methylcarbamate

Benzyl ((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)methylcarbamate

A solution of (R)-tert-butyl 3-(aminomethyl)pyrrolidine-1-carboxylate(1.0 g, 5.0 mmol) and 50 mL THF was cooled in an ice bath. To thismixture was added benzyl chloroformate (0.77 mL, 5.5 mmol), followed bytriethylamine (1.39 mL, 10 mmol). After removing the ice bath, thereaction was stirred for 4 h. The mixture was poured into ice water andextracted with EtOAc. The organic extracts were washed with water, driedover Na₂SO₄, filtered, and concentrated. Purification via silica gelchromatography using EtOAc in hexanes (0-40%) gave benzyl((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)methylcarbamate (1.29 g,77%) as a colorless oil. ¹H NMR (400 MHz, CDCl₃) δ 7.39-7.28 (m, 5H),5.10 (s, 2H), 4.87 (s, 1H), 3.52-2.95 (m, 6H), 2.41-2.35 (m, 1H),2.10-1.79 (m, 2H), 1.45 (s, 9H) ppm.

Benzyl((R)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-yl)methylcarbamate

A solution of benzyl((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)methylcarbamate (0.20 g,0.60 mmol) and 4 M HCl in dioxane (10 mL) was stirred for 3 h at roomtemperature. After evaporating the solvent under reduced pressure, theresulting solid was triturated with Et₂O and dried under vacuum, thentaken up in CH₂Cl₂ (10 mL). To this solution was added2-(4-chloro-7-methylquinazolin-2-yl)phenol (0.16 g, 0.60 mmol) andtriethylamine (0.25 mL, 1.8 mmol). The reaction mixture was stirred atroom temperature overnight, then diluted with CH₂Cl₂ and washed withwater. The CH₂Cl₂ solution was dried over Na₂SO₄, filtered, andconcentrated. Purification via silica gel chromatography using 0-40%EtOAc in hexanes gave benzyl((R)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-yl)methylcarbamateas a colorless oil (0.19 g, 68%). LC/MS: m/z 469.1 (M+H)⁺ at 2.58 min(10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)).

2-(4-((R)-3-(Aminomethyl)pyrrolidin-1-yl)-7-methylquinazolin-2-yl)phenol

A solution of benzyl((K)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-yl)methylcarbamate(0.19 g, 0.41 mmol) and MeOH (5 mL) was stirred with Pd/C (20 mg, 10%weight of Pd on carbon) under an H₂ atmosphere at ambient pressureovernight. Purification via silica gel chromatography using MeOH inCH₂Cl₂ (0-10%) gave2-(4-((R)-3-(aminomethyl)pyrrolidin-1-yl)-7-methylquinazolin-2-yl)phenol(63 mg, 45%). LC/MS: m/z 335.7 (M+H)⁺ at 1.23 min (10%-99% CH₃CN (0.035%TFA)/H₂O (0.05% TFA)).

(R)-Tetrahydrofuran-3-yl((R)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-yl)methylcarbamate

A solution of2-(4-((R)-3-(aminomethyl)pyrrolidin-1-yl)-7-methylquinazolin-2-yl)phenol(15 mg, 0.045 mmol) and CH₂Cl₂ (0.5 mL) was cooled in an ice bath. Tothis mixture was added (R)-tetrahydrofuran-3-yl chloroformate (7 μL,0.045 mmol), followed by triethylamine (13 μL, 0.090 mmol). Afterremoving the ice bath, the reaction was stirred at room temperature for3 h. Purification via preparative reverse phase HPLC (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)) gave (R)-tetrahydrofuran-3-yl((R)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-yl)methylcarbamateas the TFA salt. LC/MS: m/z 449.3 (M+H)⁺ at 2.17 min (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)).

Example 307 (S)-Tetrahydrofuran-3-yl((R)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-yl)methylcarbamate

(S)-Tetrahydrofuran-3-yl((R)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-yl)methylcarbamate

A mixture of2-(4-((R)-3-(aminomethyl)pyrrolidin-1-yl)-7-methylquinazolin-2-yl)phenol(15 mg, 0.045 mmol) and CH₂Cl₂ (0.5 mL) was cooled in an ice bath. Tothis was added (S)-tetrahydrofuran-3-yl chloroformate (7 μL, 0.045mmol), followed by triethylamine (13 μL, 0.090 mmol). After removing theice bath, the reaction was stirred at room temperature for 3 h.Purification via preparative reverse phase HPLC (10%-99% CH₃CN (0.035%TFA)/H₂O (0.05% TFA)) gave (S)-tetrahydrofuran-3-yl((R)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-yl)methylcarbamateas the TFA salt. LC/MS: m/z 449.3 (M+H)⁺ at 2.18 min (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)).

Example 308(2R)-Tetrahydro-N—(((R)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-yl)methyl)furan-2-carboxamide

(2R)-Tetrahydro-N—(((R)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-yl)methyl)furan-2-carboxamide

To a solution of2-(4-((R)-3-(aminomethyl)pyrrolidin-1-yl)-7-methylquinazolin-2-yl)phenol(15 mg, 0.045 mmol) and DMF (0.5 mL) was added(R)-tetrahydrofuran-2-carboxylic acid (6 μL, 0.062 mmol), followed bythe addition of HATU (26 mg, 67 mmol) and triethylamine (13 μL, 0.090mmol). The reaction was stirred at room temperature for 3 h.Purification via preparative reverse phase HPLC (10%-99% CH₃CN (0.035%TFA)/H₂O (0.05% TFA)) gave(2R)-tetrahydro-N-(((R)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-yl)methyl)furan-2-carboxamideas the TFA salt. LC/MS: m/z 433.5 (M+H)⁺ at 2.11 min (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)).

Example 309(R)-{1-[2-(2-Hydroxy-phenyl)-7-methyl-quinazolin-4-yl]-pyrrolidin-3-yl}-carbamicacid benzyl ester

{1-[2-(2-Hydroxy-phenyl)-7-methyl-quinazolin-4-yl]-pyrrolidin-3R-yl}-carbamicacid tert-butyl ester

To a cooled (−15° C.) solution of2-(4-chloro-7-methylquinazolin-2-yl)phenol (43.8 g, 0.15 mol) in CH₂Cl₂(125 mL) was added dropwise a solution of(3R)-(+)-3-(tert-butoxycarbonylamino)pyrrolidine (30 g, 0.16 mol) andtriethylamine (38 mL, 0.27 mol) in CH₂Cl₂ (170 mL). The addition, duringwhich the temperature stayed below 30° C., was completed in 20 minutes.The external cooling was removed and the reaction mixture was stirred atroom temperature overnight. Water (1 L) and CH₂Cl₂ (1 L) were added. Theresulting precipitate was collected by filtration, washed with water andCH₂Cl₂, and air-dried to yield 33 g of pure{1-[2-(2-hydroxy-phenyl)-7-methyl-quinazolin-4-yl]-pyrrolidin-3R-yl}-carbamicacid tert-butyl ester. The filtrates were evaporated to give anotherbatch of crude{1-[2-(2-hydroxy-phenyl)-7-methyl-quinazolin-4-yl]-pyrrolidin-3R-yl}-carbamicacid tert-butyl ester which was purified by trituration with CH₂Cl₂.Total yield: 43.5 g (70%). ¹H-NMR (300 MHz, CDCl₃): δ 8.45 (dd, J=8 Hz,1.7 Hz, 1H), 7.95 (d, J=8.8 Hz, 1H), 7.57 (s, 1H), 7.37-7.31 (m, 1H),7.18 (dd, J=8.5 Hz, 1.7, 1H), 7.0 (dd, J=8.3 Hz, 1.1 Hz, 1H), 6.9 (dt,J=8.9 Hz, 1.4 Hz, 1H), 4.77 (bs, 1H), 4.40 (bs, 1H), 4.27-4.21 (m, 1H),4.14-4.03 (m, 2H), 3.86 (dd, J=11.8 Hz, 4.4 Hz, 1H), 2.50 (s, 3H),2.34-2.28 (m, 1H), 2.08-2.02 (m, 1H), 1.46 (s, 9H) ppm.

2-(4-(3R-Aminopyrrolidin-1-yl)-7-methylquinazolin-2-yl)phenol

{1-[2-(2-Hydroxy-phenyl)-7-methyl-quinazolin-4-yl]-pyrrolidin-3R-yl}-carbamicacid tert-butyl ester (43.5 g, 100 mmol) was stirred with CF₃CO₂H (142mL) in CH₂Cl₂ (300 mL) at room temperature overnight. The solution wasconcentrated to dryness, and the residue was suspended in 10% aq. Na₂CO₃(900 mL) and stirred for 2 hours. The suspension was filtered, and theyellow solid was washed with water several times. The product wasair-dried at 45° C. to yield2-(4-(3R-aminopyrrolidin-1-yl)-7-methylquinazolin-2-yl)phenol (34.2 g)as a light-yellow solid. ¹H-NMR (300 MHz, CD₃OD): δ 8.41 (dd, J=7.4 Hz,1.4 Hz, 1H), 8.09 (d, J=8.5 Hz, 1H), 7.46 (s, 1H), 7.34-7.28 (m, 1H),7.23 (dd, J=8.8 Hz, 1.9 Hz, 1H), 6.91-6.85 (m, 2H), 4.16-4.09 (m, 2H),4.00-3.94 (m, 1H), 3.73-3.64 (m, 2H), 2.48 (s, 3H), 2.26-2.20 (m, 1H),1.92-1.86 (m, 1H) ppm.

(R)-{1-[2-(2-Hydroxy-phenyl)-7-methyl-quinazolin-4-yl]-pyrrolidin-3-yl}-carbamicacid benzyl ester

Method A

To (R)-2-[4-(3-amino-pyrrolidin-1-yl)-7-methyl-quinazolin-2-yl]-phenol(50.8 mg, 0.16 mmol) was added 500 μL of CH₂Cl₂ and the solution wascooled to 0° C. To this solution was added sequentially triethylamine(33.2 μL, 0.24 mmol) and benzyl chloroformate (29.2 mg, 0.17 mmol). Thereaction mixture was stirred from 0° C. to 5° C. over 45 min, thendiluted with water and CH₂Cl₂ (10 mL). The organic layer was separatedand dried over Na₂SO₄, and the solvent was removed under reducedpressure to give(R)-{1-[2-(2-hydroxy-phenyl)-7-methyl-quinazolin-4-yl]-pyrrolidin-3-yl}-carbamicacid benzyl ester. LC/MS: m/z 455.2 (M+H)⁺ at 2.81 min (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)).

Method B

Benzyl(R)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-ylcarbamate

To tert-butyl(R)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-ylcarbamate(398 mg, 0.94 mmol) was added 3 mL of 1:1 TFA: CH₂Cl₂. The mixture wasthen stirred at room temperature for 30 minutes. The reaction mixturewas diluted with a solution of saturated NaHCO₃ and CH₂Cl₂. The organiclayer was separated, washed with a solution of extracted 1 N NaOH, driedover Na₂SO₄ and evaporated under reduced pressure to give theintermediate amine. To this amine (300 mg, 0.94 mmol) were added 3 ml ofCH₂Cl₂ and triethylamine (145 μL, 1.04 mmol). After cooling the mixtureto 0° C., benzyl chloroformate (161.6 mg, 0.94 mmol) was added, and thereaction was stirred for 30 minutes. Purification via silica gelchromatography using 20-100% ethyl acetate/hexanes gave benzyl(R)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-ylcarbamate.LC/MS: m/z 455.2 (M+H)⁺ at 2.81 min (10%-99% CH₃CN (0.035% TFA)/H₂O(0.05% TFA)).

Benzyl(R)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-ylcarbamatehydrochloride

A 2.0 M HCl solution in Et₂O (318 μL, 0.636 mmol) was slowly added to astirring solution of benzyl(R)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-ylcarbamate(289 mg, 0.636 mmol) in 2.1 mL of CH₂Cl₂. Solvents were removed underreduced pressure and the residue was triturated with Et₂O and filteredto give benzyl(R)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-ylcarbamatehydrochloride. LC/MS: m/z 455.2 (M+H)⁺ at 2.80 min (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)).

Example 310(2R)-Tetrahydro-N—(((S)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-yl)methyl)furan-2-carboxamide

(2R)-Tetrahydro-N—(((S)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-yl)methyl)furan-2-carboxamide

To a solution of2-(4-((S)-3-(aminomethyl)pyrrolidin-1-yl)-7-methylquinazolin-2-yl)phenol(25 mg, 0.075 mmol) and DMF (0.5 mL) was added(R)-tetrahydrofuran-2-carboxylic acid (8.6 μL, 0.09 mmol), followed bythe addition of HATU (34 mg, 0.09 mmol) and triethylamine (21 μL, 0.15mmol). The reaction was stirred at room temperature for 3 h.Purification via preparative reverse phase HPLC (10%-99% CH₃CN (0.035%TFA)/H₂O (0.05% TFA)) gave(2R)-tetrahydro-N—(((S)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-yl)methyl)furan-2-carboxamideas the TFA salt. LC/MS: m/z 433.5 (M+H)⁺ at 2.13 min (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)).

Example 311N—(((S)-1-(2-(2-Hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-yl)methyl)cyclopropanecarboxamide

N—(((S)-1-(2-(2-Hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-yl)methyl)cyclopropanecarboxamide

A solution of2-(4-((S)-3-(aminomethyl)pyrrolidin-1-yl)-7-methylquinazolin-2-yl)phenol(25 mg, 0.075 mmol) and CH₂Cl₂ (0.5 mL) was cooled in an ice bath. Tothis mixture was added cyclopropanecarbonyl chloride (7.5 μL, 82 mmol),followed by triethylamine (21 μL, 0.15 mmol). After removing the icebath, the reaction was stirred at room temperature for 3 h. Purificationvia preparative reverse phase HPLC (10%-99% CH₃CN (0.035% TFA)/H₂O(0.05% TFA)) gaveN—(((S)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-yl)methyl)cyclopropanecarboxamideas the TFA salt. LC/MS: m/z 403.7 (M+H)⁺ at 2.17 min (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)).

Example 312 (R)-Cyclopropanecarboxylic acid{1-[2-(2-hydroxy-phenyl)-7-methyl-quinazolin-4-yl]-pyrrolidin-3-yl}-amide

(R)-Cyclopropanecarboxylic acid{1-[2-(2-hydroxy-phenyl)-7-methyl-quinazolin-4-yl]-pyrrolidin-3-yl}-amide

To (R)-2-[4-(3-amino-pyrrolidin-1-yl)-7-methyl-quinazolin-2-yl]-phenol(49.3 mg, 0.15 mmol) was added 500 μL of CH₂Cl₂ and the solution wascooled to 0° C. To this solution was added sequentially triethylamine(21.5 μL, 0.15 mmol) and cyclopropanecarbonyl chloride (16.1 mg, 0.15mmol). The reaction mixture was stirred from 0° C. to 5° C. over 40 minand diluted with water and CH₂Cl₂ (10 mL). The organic layer wasseparated and dried over Na₂SO₄, and the solvent was removed underreduced pressure. The residue was purified via preparative reverse phaseHPLC using 10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA) to give(R)-cyclopropanecarboxylic acid{1-[2-(2-hydroxy-phenyl)-7-methyl-quinazolin-4-yl]-pyrrolidin-3-yl}-amideas the TFA salt. LC/MS: m/z 389 (M+H)⁺ at 2.38 min (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)).

Example 313(R)-{1-[2-(2-Hydroxy-phenyl)-7-methyl-quinazolin-4-yl]-pyrrolidin-3-yl}-carbamicacid phenyl ester

(R)-{1-[2-(2-Hydroxy-phenyl)-7-methyl-quinazolin-4-yl]-pyrrolidin-3-yl}-carbamicacid phenyl ester

To (R)-2-[4-(3-amino-pyrrolidin-1-yl)-7-methyl-quinazolin-2-yl]-phenol(48 mg, 0.15 mmol) was added 500 μL of CH₂Cl₂, and the solution wascooled to 0° C. To this solution was added sequentially triethylamine(21 μL, 0.15 mmol) and phenyl chloroformate (22.8 mg, 0.15 mmol). Thereaction mixture was stirred from 0° C. to 5° C. over 40 min, dilutedwith water and CH₂Cl₂ (10 mL). The organic layer was separated and driedover Na₂SO₄, and the solvent was removed under reduced pressure. Theresidue was purified via preparative reverse phase HPLC using 10%-99%CH₃CN (0.035% TFA)/H₂O (0.05% TFA) to give(R)-{1-[2-(2-hydroxy-phenyl)-7-methyl-quinazolin-4-yl]-pyrrolidin-3-yl}-carbamicacid phenyl ester as the TFA salt. LC/MS: m/z 441 (M+H)⁺ at 2.78 min(10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)).

Example 314 (Tetrahydro-2H-pyran-2-yl)methyl(R)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-ylcarbamate

(Tetrahydro-2H-pyran-2-yl)methyl 1H-imidazole-1-carboxylate

To a mixture of (tetrahydro-2H-pyran-2-yl)methanol (369 mg, 3.17 mmol)and di(1H-imidazol-1-yl)methanone (1.03 g, 6.35 mmol) was added 10.5 mLof CH₂Cl₂. The reaction was stirred at 50° C. for 3 hours. The reactionmixture was used without further purification. LC/MS: m/z 211.1 (M+H)⁺at 0.94 min (10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)).

(Tetrahydro-2H-pyran-2-yl)methyl(R)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-ylcarbamate

To a mixture of2-(4-((R)-3-aminopyrrolidin-1-yl)-7-methylquinazolin-2-yl)phenol (100mg, 0.31 mmol) and (tetrahydro-2H-pyran-2-yl)methyl1H-imidazole-1-carboxylate (98 mg, 0.47 mmol) was added 1.04 mL CH₂Cl₂and triethylamine (65 μL, 47 mg, 0.46 mmol). The mixture was stirred atroom temperature overnight. An additional equivalent of(tetrahydro-2H-pyran-2-yl)methyl 1H-imidazole-1-carboxylate (100 mg,0.47 mmol) was added to the mixture, and the reaction was heated at 45°C. for 4 hours. Purification via silica gel chromatography using10%-100% ethyl acetate/hexanes gave (tetrahydro-2H-pyran-2-yl)methyl(R)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-ylcarbamate.LC/MS: m/z 463.4 (M+H)⁺ at 2.66 min (10%-99% CH₃CN (0.035% TFA)/H₂O(0.05% TFA)).

Example 315 (R)-5-Oxo-pyrrolidine-2-carboxylic acid{1-[2-(2-hydroxy-phenyl)-7-methyl-quinazolin-4-yl]-pyrrolidin-3-yl}-amide

(R)-5-Oxo-pyrrolidine-2-carboxylic acid{1-[2-(2-hydroxy-phenyl)-7-methyl-quinazolin-4-yl]-pyrrolidin-3-yl}-amide

To (R)-2-[4-(3-amino-pyrrolidin-1-yl)-7-methyl-quinazolin-2-yl]-phenol(71 mg, 0.22 mmol) was added 890 μL of CH₂Cl₂. To this solution wasadded sequentially triethylamine (47 μL, 0.34 mmol) and5-oxo-pyrrolidine-2-carboxylic acid (34.8 mg, 0.27 mmol) and BOP (119mg, 0.27 mmol). The reaction mixture was stirred at room temperature for2 h and diluted with water and CH₂Cl₂ (10 mL). The organic layer wasseparated and dried over Na₂SO₄, and the solvent was removed underreduced pressure to give (R)-5-oxo-pyrrolidine-2-carboxylic acid{1-[2-(2-hydroxy-phenyl)-7-methyl-quinazolin-4-yl]-pyrrolidin-3-yl}-amide.LC/MS: m/z 432.5 (M+H)⁺ at 2.24 min (10%-99% CH₃CN (0.035% TFA)/H₂O(0.05% TFA)).

Example 316Tetrahydro-N—((R)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-yl)-2H-pyran-4-carboxamide

Tetrahydro-N—((R)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-yl)-2H-pyran-4-carboxamide

To a stirred solution of2-(4-((R)-3-aminopyrrolidin-1-yl)-7-methylquinazolin-2-yl)phenol (50 mg,0.16 mmol) in 1 mL of DMF was cooled to 0° C. andtetrahydro-2H-pyran-4-carboxylic acid (24 mg, 0.19 mmol) was added,followed by the addition of triethylamine (32 mg, 44 μL, 0.31 mmol) andHATU (71.1 mg, 0.187 mmol). The reaction was stirred at 0° C. for 10minutes, then gradually warmed to room temperature, then filtered.Purification via reverse phase HPLC (10%-99% CH₃CN (0.035% TFA)/H₂O(0.05% TFA)) gavetetrahydro-N—((R)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-yl)-2H-pyran-4-carboxamideas the TFA salt. LC/MS: m/z 433.5 (M+H)⁺ at 2.05 min (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)).

Example 3172-(Tetrahydro-2H-pyran-4-yl)-N—((R)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-yl)acetamide

2-(Tetrahydro-2H-pyran-4-yl)-N—((R)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-yl)acetamide

To a stirred solution of2-(4-((R)-3-aminopyrrolidin-1-yl)-7-methylquinazolin-2-yl)phenol (50 mg,0.16 mmol) in 1 mL of DMF cooled to 0° C. was added2-(tetrahydro-2H-pyran-4-yl)acetic acid (27 mg, 0.19 mmol), followed bythe addition of triethylamine (32 mg, 44 μL, 0.31 mmol) and HATU (71.1mg, 0.187 mmol). The reaction was stirred at 0° C. for 10 minutes, thengradually warmed to room temperature. Filtered, and purified via reversephase HPLC (10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)) to give2-(tetrahydro-2H-pyran-4-yl)-N—((R)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-yl)acetamideas the TFA salt. LC/MS: m/z 477.3 (M+H)⁺ at 2.07 min (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)).

Example 318N—((R)-1-(2-(2-Hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-yl)-3-(pyridin-2-yl)propanamide

N—((R)-1-(2-(2-Hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-yl)-3-(pyridin-2-yl)propanamide

To a solution of2-(4-((R)-3-aminopyrrolidin-1-yl)-7-methylquinazolin-2-yl)phenol (0.05g, 0.15 mmol) in DMF (1 mL) was added 3-(pyridin-2-yl)propanoic acid (30mg, 0.195 mmol), followed by the addition of triethylamine (42 μL, 0.30mmol) and HATU (74 mg, 0.195 mmol). The reaction was stirred at roomtemperature for 2 h and then purified via reverse phase HPLC (10%-99%CH₃CN (0.035% TFA)/H₂O (0.05% TFA)) to obtainN—((R)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-yl)-3-(pyridin-2-yl)propanamideas the TFA salt. LC/MS: m/z 454.3 (M+H)⁺ at 1.79 min (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)).

Example 319 (Pyridin-3-yl)methyl(R)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-ylcarbamate

(Pyridin-3-yl)methyl(R)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-ylcarbamate

To a solution of2-(4-((R)-3-aminopyrrolidin-1-yl)-7-methylquinazolin-2-yl)phenol (50 mg,0.16 mmol) in DMSO (0.5 mL) at room temperature was added triethylamine(43 μL, 0.31 mmol), followed by the addition of (pyridin-3-yl)methyl1H-imidazole-1-carboxylate (63 mg, 0.31 mmol). The reaction was stirredat room temperature overnight, filtered, and purified using reversephase HPLC (10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)) to afford(pyridin-3-yl)methyl(R)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-ylcarbamateas the TFA salt. LC/MS: m/z 456.5 (M+H)⁺ at 1.85 min (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)).

Example 320 (Pyridin-4-yl)methyl(R)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-ylcarbamate

(Pyridin-4-yl)methyl(R)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-ylcarbamate

To a solution of2-(4-((R)-3-aminopyrrolidin-1-yl)-7-methylquinazolin-2-yl)phenol (50 mg,0.16 mmol) in DMSO (0.5 mL) at room temperature was added triethylamine(43 μL, 0.31 mmol), followed by the addition of (pyridin-4-yl)methyl1H-imidazole-1-carboxylate (63 mg, 0.31 mmol). The reaction was stirredat room temperature overnight, filtered, and purified using reversephase HPLC (10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)) to afford(pyridin-4-yl)methyl(R)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-ylcarbamateas the TFA salt. LC/MS: m/z 456.5 (M+H)⁺ at 1.84 min (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)).

Example 321 (Benzo[d][1,3]dioxol-7-yl)methyl(R)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-ylcarbamate

(Benzo[d][1,3]dioxol-7-yl)methyl(R)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-ylcarbamate

To a solution of2-(4-((R)-3-aminopyrrolidin-1-yl)-7-methylquinazolin-2-yl)phenol (50 mg,0.16 mmol) in DMSO (0.5 mL) was added triethylamine (43 μL, 0.31 mmol),followed by the addition of (benzo[d][1,3]dioxol-4-yl)methyl1H-imidazole-1-carboxylate (77 mg, 0.31 mmol). The reaction was stirredat room temperature overnight, filtered, and purified using reversephase HPLC (10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)) to afford(benzo[d][1,3]dioxol-7-yl)methyl(R)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-ylcarbamateas the TFA salt. LC/MS: m/z 499.3 (M+H)⁺ at 2.57 min (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)).

Example 322N—((R)-1-(2-(2-Hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-yl)-3-(pyridin-3-yl)propanamide

N—((R)-1-(2-(2-Hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-yl)-3-(pyridin-3-yl)propanamide

2-(4-((R)-3-Aminopyrrolidin-1-yl)-7-methylquinazolin-2-yl)phenol (249mg, 0.778 mmol) was dissolved in 2.6 mL of CH₂Cl₂.3-(Pyridin-3-yl)propanoic acid (129 mg, 0.85 mmol) was added followed bytriethylamine (102 mg, 141 μL, 1.01 mmol) and BOP (378 mg, 0.85 mmol).After stirring the reaction for 35 minutes at room temperature, it wasfiltered, and purified by reverse phase HPLC (10%-99% CH₃CN (0.035%TFA)/H₂O (0.05% TFA)) to giveN—((R)—-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-yl)-3-(pyridin-3-yl)propanamideas the TFA salt. LC/MS: m/z 454.4 (M+H)⁺ at 2.08 min (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)).

Example 323(R)-3-Cyclopentyl-N-{1-[2-(2-hydroxy-phenyl)-7-methyl-quinazolin-4-yl]-pyrrolidin-3-yl}-propionamide

(R)-3-Cyclopentyl-N-{1-[2-(2-hydroxy-phenyl)-7-methyl-quinazolin-4-yl]-pyrrolidin-3-yl}-propionamide

To (R)-2-[4-(3-amino-pyrrolidin-1-yl)-7-methyl-quinazolin-2-yl]-phenol(100 mg, 0.31 mmol) was added 1 mL of CH₂Cl₂, and the solution wascooled to 0° C. To this solution was added sequentially triethylamine(56.6 μL, 0.41 mmol) and 3-cyclopentyl-propionyl chloride (57 mg, 0.35mmol). The reaction mixture was stirred at room temperature for 2 h,then diluted with water and CH₂Cl₂ (10 mL). The organic layer wasseparated and dried over Na₂SO₄, and the solvent was removed underreduced pressure. The residue was purified via preparative reverse phaseHPLC using 10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA) to give((R)-3-cyclopentyl-N-{1-[2-(2-hydroxy-phenyl)-7-methyl-quinazolin-4-yl]-pyrrolidin-3-yl}-propionamideas the TFA salt. LC/MS: m/z 445.4 (M+H)⁺ at 2.85 min (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)).

Example 324(R)—N-{1-[2-(2-Hydroxy-phenyl)-7-methyl-quinazolin-4-ylPpyrrolidin-3-yl}-3-piperidin-1-yl-propionamide

(R)—N-{1-[2-(2-Hydroxy-phenyl)-7-methyl-quinazolin-4-ylPpyrrolidin-3-yl}-3-piperidin-1-yl-propionamide

To (R)-2-[4-(3-amino-pyrrolidin-1-yl)-7-methyl-quinazolin-2-yl]-phenol(58.6 mg, 0.18 mmol) was added 700 μL of CH₂Cl₂. To this solution wasadded sequentially triethylamine (38.3 μL, 0.27 mmol),3-piperidin-1-yl-propionic acid (37.4 mg, 0.24 mmol) and BOP (119 mg,0.27 mmol). The reaction mixture was stirred at room temperature for 2 hand diluted with water and CH₂Cl₂ (10 mL). The organic layer wasseparated and dried over Na₂SO₄, and the solvent was removed underreduced pressure. The residue was purified via preparative reverse phaseHPLC using 10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA) to give(R)—N-{1-[2-(2-hydroxy-phenyl)-7-methyl-quinazolin-4-yl]-pyrrolidin-3-yl}-3-piperidin-1-yl-propionamideas the TFA salt. LC/MS: m/z 460.4 (M+H)⁺ at 2.1 min (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)).

Example 325N—((R)-1-(2-(2-Hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-yl)-3-(trifluoromethoxy)benzamide

N—((R)-1-(2-(2-Hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-yl)-3-(trifluoromethoxy)benzamide

To a stirring solution of2-(4-((R)-3-aminopyrrolidin-1-yl)-7-methylquinazolin-2-yl)phenol (32 mg,0.10 mmol) and DMF (1.0 mL) was added 3-(trifluoromethoxy)benzoylchloride (19 μL, 0.10 mmol), followed by the addition of triethylamine(28 μL, 0.2 mmol). The reaction was stirred at room temperatureovernight, filtered, and purified via preparative reverse phase HPLC(10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)) to giveN—((R)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-yl)-3-(trifluoromethoxy)benzamideas the TFA salt. LC/MS: m/z 509.5 (M+H)⁺ at 2.71 min (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)).

Example 326N—((R)-1-(2-(2-Hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-yl)-3-methoxybenzamide

N—((R)-1-(2-(2-Hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-yl)-3-methoxybenzamide

To a stirring solution of2-(4-((R)-3-aminopyrrolidin-1-yl)-7-methylquinazolin-2-yl)phenol (32 mg,0.10 mmol) and DMF (1.0 mL) was added 3-methoxybenzoyl chloride (14 μL,0.1 mmol), followed by the addition of triethylamine (28 μL, 0.2 mmol).The reaction was stirred at room temperature overnight, then filtered,and purified via preparative reverse phase HPLC (10%-99% CH₃CN (0.035%TFA)/H₂O (0.05% TFA)) to giveN—((R)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-yl)-3-methoxybenzamideas the TFA salt. LC/MS: m/z 455.3 (M+H)⁺ at 2.43 min (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)).

Example 3273-Cyano-N—((R)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-yl)benzamide

3-Cyano-N—((R)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-yl)benzamide

To a stirring solution of2-(4-((R)-3-aminopyrrolidin-1-yl)-7-methylquinazolin-2-yl)phenol (32 mg,0.10 mmol) and DMF (1.0 mL) was added 3-cyanobenzoyl chloride (17 mg,0.10 mmol), followed by the addition of triethylamine (28 μL, 0.20mmol). The reaction was stirred at room temperature overnight, thenfiltered, and purified via preparative reverse phase HPLC (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)) to give3-cyano-N—((R)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-yl)benzamideas the TFA salt. LC/MS: m/z 450.3 (M+H)⁺ at 2.39 min (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)).

Example 328N—((R)-1-(2-(2-Hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-yl)nicotinamide

N—((R)-1-(2-(2-Hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-yl)nicotinamide

To a stirring solution of2-(4-((R)-3-aminopyrrolidin-1-yl)-7-methylquinazolin-2-yl)phenol (32 mg,0.1 mmol) and DMF (1.0 mL) was added nicotinoyl chloride (18 mg, 0.1mmol), followed by the addition of triethylamine (28 μL, 0.2 mmol). Thereaction was stirred at room temperature overnight, then filtered, andpurified via preparative reverse phase HPLC (10%-99% CH₃CN (0.035%TFA)/H₂O (0.05% TFA)) to giveN—((R)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-yl)nicotinamideas the TFA salt. LC/MS: m/z 426.3 (M+H)⁺ at 1.91 min (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)).

Example 329N—((R)-1-(6-Fluoro-2-(2-hydroxyphenyl)quinazolin-4-yl)pyrrolidin-3-yl)cyclopropanecarboxamide

Method A

2-(4-Chloro-6-fluoroquinazolin-2-yl)phenol

A solution of 4-chloro-6-fluoro-2-(2-methoxyphenyl)quinazoline (3.0 g,10.39 mmol) in CH₂Cl₂ (15 mL) was cooled to −78° C. To it was added a1.0 M BBr₃ solution in CH₂Cl₂ (52 mL, 52 mmol) dropwise. The reactionwas allowed to warm to room temperature. It was neutralized with asaturated aqueous NaHCO₃ solution, and the aqueous layer was extractedtwice with CH₂Cl₂. The combined organic layers were dried over MgSO₄,filtered, and concentrated. Purification via silica gel chromatographyusing 5-20% CH₂Cl₂/hexanes gave2-(4-chloro-6-fluoroquinazolin-2-yl)phenol (1.68 g, 60%). LC/MS: m/z275.3 (M+H)⁺ at 3.39 min (10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)).

tert-Butyl(R)-1-(6-fluoro-2-(2-hydroxyphenyl)quinazolin-4-yl)pyrrolidin-3-ylcarbamate

At 0° C. under an N₂ atmosphere, a solution of tert-butyl(R)-pyrrolidin-3-ylcarbamate (264 mg, 1.42 mmol) and triethylamine (0.33mL, 2.36 mmol) in CH₂Cl₂ was rapidly added to a stirring solution of2-(4-chloro-6-fluoroquinazolin-2-yl)phenol (325 mg, 1.18 mmol) in 15 mLCH₂Cl₂. The reaction mixture was stirred for 1 h before it was quenchedwith water, and the aqueous layer was extracted twice with CH₂Cl₂. Thecombined organic extracts were dried over MgSO₄, filtered, andconcentrated. Purification via silica gel chromatography using 0-10%EtOAc/CH₂Cl₂ yielded tert-butyl(R)-1-(6-fluoro-2-(2-hydroxyphenyl)quinazolin-4-yl)pyrrolidin-3-ylcarbamate.LC/MS: m/z 425.5 (M+H)⁺ at 2.74 min (10%-99% CH₃CN (0.035% TFA)/H₂O(0.05% TFA)).

2-(4-((R)-3-Aminopyrrolidin-1-yl)-6-fluoroquinazolin-2-yl)phenol

To a solution of tert-butyl(R)-1-(6-fluoro-2-(2-hydroxyphenyl)quinazolin-4-yl)pyrrolidin-3-ylcarbamate(480 mg, 1.11 mmol) in CH₂Cl₂ (10 mL) was added TFA (4 mL). The reactionwas stirred for an hour, diluted with 10 mL CH₂Cl₂, and neutralized witha saturated aqueous NaHCO₃ solution. The aqueous layer was extractedtwice with CH₂Cl₂. The combined organic layers were dried over MgSO₄,filtered, and concentrated. Purification via silica gel chromatographyusing 3-20% EtOAc/CH₂Cl₂ gave2-(4-((R)-3-aminopyrrolidin-1-yl)-6-fluoroquinazolin-2-yl)phenol. LC/MS:m/z 325.5 (M+H)⁺ at 1.26 min (10%-99% CH₃CN (0.035% TFA)/H₂O (0.05%TFA)).

N—((R)-1-(6-Fluoro-2-(2-hydroxyphenyl)quinazolin-4-yl)pyrrolidin-3-yl)cyclopropanecarboxamide

To a solution of2-(4-((R)-3-aminopyrrolidin-1-yl)-6-fluoroquinazolin-2-yl)phenol (0.025g, 0.08 mmol) in DMF (1.0 mL) was added cyclopropanecarboxylic acid (10mg, 0.12 mmol), followed by the addition of triethylamine (22 μL, 0.16mmol) and HATU (40 mg, 0.1 mmol). The reaction was stirred at roomtemperature for 2 h, filtered, and purified using reverse phase HPLC(10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)) to obtainN—((R)-1-(6-fluoro-2-(2-hydroxyphenyl)quinazolin-4-yl)pyrrolidin-3-yl)cyclopropanecarboxamideas the TFA salt. LC/MS: m/z 393.3 (M+H)⁺ at 2.23 min (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)).

Method B

Benzyl (R)-1-(tert-butoxycarbonyl)pyrrolidin-3-ylcarbamate

At −10° C., triethylamine (2.3 mL, 16.6 mmol) was added to a solution ofbenzyl (R)-pyrrolidin-3-ylcarbamate oxalate (2.0 g, 6.4 mmol) in MeOH,followed by the slow addition of Boc₂O (1.92 mL, 8.3 mmol). The reactionwas allowed to warm to room temperature and was stirred overnight. Themixture was quenched with water and extracted twice with CH₂Cl₂. Thecombined organic layers were dried over MgSO₄, filtered, andconcentrated. Purification via silica gel chromatography using 0-10%EtOAc in CH₂Cl₂ gave benzyl(R)-1-(tert-butoxycarbonyl)pyrrolidin-3-ylcarbamate (1.85 g, 90%).LC/MS: m/z 321.3 (M+H)⁺ at 3.01 min (10%-99% CH₃CN (0.035% TFA)/H₂O(0.05% TFA)).

(R)-tert-Butyl 3-aminopyrrolidine-1-carboxylate

Under an N₂ atmosphere, a solution of benzyl(R)-1-(tert-butoxycarbonyl)pyrrolidin-3-ylcarbamate (1.85 g, 5.75 mmol)in 10 mL MeOH was added to a flask containing Pd/C (185 mg, 10% weightPd on carbon). After evacuating the flask under vacuum and purging ittwice with N₂, the reaction was stirred for 3 h under an H₂ atmosphereat ambient pressure. The reaction was filtered through a bed of Celite,and the solvent was evaporated under reduced pressure to obtain(R)-tert-butyl 3-aminopyrrolidine-1-carboxylate which was used withoutfurther purification. LC/MS: m/z 187.3 (M+H)⁺ at 1.07 min (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)).

(R)-tert-Butyl 3-(cyclopropanecarboxamido)pyrrolidine-1-carboxylate

To a mixture of (R)-tert-butyl 3-aminopyrrolidine-1-carboxylate (500 mg,2.68 mmol) in CH₂Cl₂ (101 mL) was added cyclopropanecarboxylic acid (276μL, 3.48 mmol), followed by the addition of HATU (1.3 g, 3.48 mmol) andtriethylamine (725 μL, 5.2 mmol). The reaction was complete afterstirring for 1 h. After quenching with water, the aqueous layer wasextracted twice with CH₂Cl₂, and the combined organic extracts weredried over MgSO₄, filtered, and concentrated. The crude material waspurified via silica gel chromatography 0-20% EtOAc/CH₂Cl₂ to afford(R)-tert-butyl 3-(cyclopropanecarboxamido)pyrrolidine-1-carboxylate (500mg, 73%). LC/MS: m/z 255.3 (M+H)⁺ at 2.33 min (10%-99% CH₃CN (0.035%TFA)/H₂O (0.05% TFA)).

N—((R)-Pyrrolidin-3-yl)cyclopropanecarboxamide

TFA (1 mL) was added to a solution of (R)-tert-butyl3-(cyclopropanecarboxamido)pyrrolidine-1-carboxylate (500 mg, 1.96 mmol)in 5 mL CH₂Cl₂. After stirring for 30 min, the reaction was quenchedwith 1M NaOH solution till neutral and extracted twice with EtOAc. Theorganic extracts were combined, dried over MgSO₄, filtered, andconcentrated to yield N—((R)-pyrrolidin-3-yl)cyclopropanecarboxamide(250 mg) which was used without further purification. LC/MS: m/z 155.3(M+H)⁺ at 0.6 min (10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)).

N—((R)-1-(6-Fluoro-2-(2-hydroxyphenyl)quinazolin-4-yl)pyrrolidin-3-yl)cyclopropanecarboxamide

A mixture of N—((R)-pyrrolidin-3-yl)cyclopropanecarboxamide (250 mg,0.86 mmol), 2-(4-chloro-6-fluoroquinazolin-2-yl)phenol (250 mg, 0.86mmol) and triethylamine (0.240 mL, 1.72 mmol) in CH₂Cl₂ (10 mL) wasstirred at room temperature. The reaction was complete after one hour.The reaction was quenched with water, the aqueous layer was extractedtwice with CH₂Cl₂, and the combined organic extracts were dried-overMgSO₄, filtered, and concentrated. Purification via silica gelchromatography using 0-10% EtOAc/CH₂Cl₂ gaveN—((R)-1-(6-fluoro-2-(2-hydroxyphenyl)quinazolin-4-yl)pyrrolidin-3-yl)cyclopropanecarboxamide(230 mg, 68%). LC/MS: m/z 393.3 (M+H)⁺ at 2.35 min (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)). ¹H NMR (400 MHz, DMSO-d6) δ 8.42-8.46 (m,2H), 8.03 (dd, J=10.5, 2.6 Hz, 1H), 7.88-7.92 (m, 1H), 7.74-7.79 (m,1H), 7.35-7.39 (m, 1H), 6.92-6.96 (m, 2H), 4.44-4.47 (m, 1H), 4.01-4.28(m, 3H), 3.83-3.87 (m, 1H), 2.20-2.28 (m, 1H), 1.99-2.06 (m, 1H),1.51-1.57 (m, 1H), 0.63-0.73 (m, 4H) ppm.

N—((R)-1-(6-Fluoro-2-(2-hydroxyphenyl)quinazolin-4-yl)pyrrolidin-3-yl)cyclopropanecarboxamidehydrochloride

To a solution ofN—((R)-1-(6-fluoro-2-(2-hydroxyphenyl)quinazolin-4-yl)pyrrolidin-3-yl)cyclopropanecarboxamide(225 mg, 0.57 mmol) in 5 mL CH₂Cl₂ was added a 2 M HCl solution in ether(0.28 mL, 0.57 mmol), which resulted in the precipitation of a solid.After the addition of 20 mL ether, the reaction mixture was stirred for1 h. The solvents were evaporated under reduced pressure to affordN—((R)-1-(6-fluoro-2-(2-hydroxyphenyl)quinazolin-4-yl)pyrrolidin-3-yl)cyclopropanecarboxamidehydrochloride (225 mg, 91%). LC/MS: m/z 393.3 (M+H)⁺ at 2.43 min(10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)). ¹H NMR (400 MHz, DMSO-d6)δ 8.23 (d, J=8.3 Hz, 1H), 8.04 (d, J=10.6 Hz, 1H), 7.91-7.94 (m, 1H),7.79-7.83 (m, 1H), 7.44-7.48 (m, 1H), 7.00-7.03 (m, 2H), 4.44 (t, J=4.9Hz, 1H), 4.09-4.23 (m, 3H), 3.87-3.90 (m, 1H), 2.25-2.34 (m, 1H),2.02-2.09 (m, 1H), 1.49-1.55 (m, 1H), 0.68-0.71 (m, 4H) ppm.

Example 330(2S)—N—((R)-1-(2-(2-Hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-yl)-2-phenylcyclopropanecarboxamide

(2S)—N—((R)-1-(2-(2-Hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-yl)-2-phenylcyclopropanecarboxamide

2-(4-((R)-3-Aminopyrrolidin-1-yl)-7-methylquinazolin-2-yl)phenol (50 mg,0.16 mmol) was dissolved in 260 μL of anhydrous CH₂Cl₂ and cooled to 0°C. (2R)-2-Phenylcyclopropanecarbonyl chloride (31 mg, 0.17 mmol)dissolved in 260 μL of anhydrous CH₂Cl₂ was added dropwise to themixture followed by triethylamine (21 mg, 28 μL, 0.20 mmol). Thereaction was stirred for 20 minutes at 0° C. and purified via reversephase HPLC (10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)) to give(2S)—N—((R)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-yl)-2-phenylcyclopropanecarboxamideas the TFA salt. LC/MS (10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)),LC/MS: m/z 465.4 (M+H)⁺ at 2.88 min (10%-99% CH₃CN (0.035% TFA)/H₂O(0.05% TFA)).

Example 3312-Chloro-6-fluoro-N—((R)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-yl)benzamide

2-Chloro-6-fluoro-N—((R)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-yl)benzamide

2-(4-((R)-3-Aminopyrrolidin-1-yl)-7-methylquinazolin-2-yl)phenol (50 mg,0.16 mmol) was dissolved in 260 μL of anhydrous CH₂Cl₂ and cooled to 0°C. 2-Chloro-6-fluorobenzoyl chloride (36 mg, 0.18 mmol) dissolved in 260μL of anhydrous CH₂Cl₂ was added dropwise to the mixture followed bytriethylamine (21 mg, 28 μL, 0.20 mmol). The reaction was stirred for 20minutes at 0° C. and purified via reverse phase HPLC (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)) to give2-chloro-6-fluoro-N—((R)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-yl)benzamideas the TFA salt. LC/MS: m/z 477.3 (M+H)⁺ at 2.81 min (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)).

Example 3324-Fluoro-3-(trifluoromethyl)-N—((R)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-yl)benzamide

4-Fluoro-3-(trifluoromethyl)-N—((R)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-yl)benzamide

2-(4-((R)-3-Aminopyrrolidin-1-yl)-7-methylquinazolin-2-yl)phenol (50 mg,0.16 mmol) was dissolved in 260 μL of anhydrous CH₂Cl₂ and cooled to 0°C. 4-Fluoro-3-(trifluoromethyl)benzoyl chloride (42 mg, 0.18 mmol)dissolved in 260 μL of anhydrous CH₂Cl₂ was added dropwise to themixture followed by triethylamine (21 mg, 28 μL, 0.20 mmol). Thereaction was stirred for 20 minutes at 0° C. and purified via reversephase HPLC (10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)) to give4-fluoro-3-(trifluoromethyl)-N—((R)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-yl)benzamideas the TFA salt. LC/MS: m/z 511.5 (M+H)⁺ at 3.07 min (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)).

Example 3333-Fluoro-N—((R)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-yl)benzamide

3-Fluoro-N—((R)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-yl)benzamide

2-(4-((R)-3-Aminopyrrolidin-1-yl)-7-methylquinazolin-2-yl)phenol (50 mg,0.16 mmol) was dissolved in 260 μL of anhydrous CH₂Cl₂ and cooled to 0°C. 3-Fluorobenzoyl chloride (30 mg, 0.18 mmol) dissolved in 260 μL ofanhydrous CH₂Cl₂ was added dropwise to the mixture followed bytriethylamine (21 mg, 28 μL, 0.20 mmol). The reaction was stirred for 20minutes at 0° C. and purified via reverse phase HPLC (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)) to give3-fluoro-N—((R)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-yl)benzamideas the TFA salt. LC/MS: m/z 443.5 (M+H)⁺ at 2.83 min (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)).

Example 3343-Fluoro-4-(trifluoromethyl)-N—((R)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-yl)benzamide

3-Fluoro-4-(trifluoromethyl)-N—((R)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-yl)benzamide

2-(4-((R)-3-Aminopyrrolidin-1-yl)-7-methylquinazolin-2-yl)phenol (50 mg,0.16 mmol) was dissolved in 260 μL of anhydrous CH₂Cl₂ and cooled to 0°C. 3-Fluoro-4-(trifluoromethyl)benzoyl chloride (42 mg, 0.18 mmol)dissolved in 260 μL of anhydrous CH₂Cl₂ was added dropwise to themixture followed by triethylamine (21 mg, 28 μL, 0.20 mmol). Thereaction was stirred for 20 minutes at 0° C. and purified via reversephase HPLC (10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)) to give3-fluoro-4-(trifluoromethyl)-N—((R)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-yl)benzamideas the TFA salt. LC/MS: m/z 511.5 (M+H)⁺ at 3.1 min (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)).

Example 335 (S)-Tetrahydrofuran-3-yl(R)-1-(6-fluoro-2-(2-hydroxyphenyl)quinazolin-4-yl)pyrrolidin-3-ylcarbamate

(S)-Tetrahydrofuran-3-yl(R)-1-(6-fluoro-2-(2-hydroxyphenyl)quinazolin-4-yl)pyrrolidin-3-ylcarbamate

A solution of2-(4-((R)-3-aminopyrrolidin-1-yl)-6-fluoroquinazolin-2-yl)phenol (0.03g, 0.092 mmol) in DMF (1.0 mL) was cooled to −40° C. To this mixture wasadded triethylamine (26 μL, 0.184 mmol), followed by the addition of(S)-tetrahydrofuran-3-yl chloroformate (0.014 g, 0.092 mmol). Afterallowing the reaction to warm to room temperature the mixture wasfiltered, and purified via reverse phase HPLC (10%-99% CH₃CN (0.035%TFA)/H₂O (0.05% TFA)) to obtain (S)-tetrahydrofuran-3-yl(R)-1-(6-fluoro-2-(2-hydroxyphenyl)quinazolin-4-yl)pyrrolidin-3-ylcarbamateas the TFA salt. LC/MS: m/z 439.5 (M+H)⁺ at 2.25 min (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)).

Method B

(S)-Tetrahydrofuran-3-yl(R)-1-(tert-butoxycarbonyl)pyrrolidin-3-ylcarbamate

To a solution of (R)-tert-butyl 3-aminopyrrolidine-1-carboxylate (500mg, 2.6 mmol) in 5 mL CH₂Cl₂ was added triethylamine (0.73 mL, 5.2mmol), and the reaction was cooled to −20° C. (S)-tetrahydrofuran-3-ylchloroformate (525 mg, 3.48 mmol) was added in portions over a period of10 minutes to the above reaction mixture. After allowing the reaction towarm to room temperature, it was quenched with water and extracted twicewith CH₂Cl₂. The combined organic layers were dried over MgSO₄,filtered, and concentrated to afford (S)-tetrahydrofuran-3-yl(R)-1-(tert-butoxycarbonyl)pyrrolidin-3-ylcarbamate. Purification viasilica gel chromatography using 0-20% EtOAc in CH₂Cl₂ gave(S)-tetrahydrofuran-3-yl(R)-1-(tert-butoxycarbonyl)pyrrolidin-3-ylcarbamate (490 mg, 63%).LC/MS: m/z 301.3 (M+H)⁺ at 2.35 min (10%-99% CH₃CN (0.035% TFA)/H₂O(0.05% TFA)).

(S)-Tetrahydrofuran-3-yl (R)-pyrrolidin-3-ylcarbamate

TFA (1 mL) was added to a solution of (S)-tetrahydrofuran-3-yl(R)-1-(tert-butoxycarbonyl)pyrrolidin-3-ylcarbamate (490 mg, 1.63 mmol)in 5 μL CH₂Cl₂. After stirring for 30 min, the reaction was quenchedwith NaOH and extracted twice with EtOAc. The organic extracts werecombined, dried over MgSO₄, filtered, and concentrated to yield(S)-tetrahydrofuran-3-yl (R)-pyrrolidin-3-ylcarbamate (230 mg) which wasused without further purification. LC/MS: m/z 201.3 (M+H)⁺ at 0.59 min(10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)).

(S)-Tetrahydrofuran-3-yl(R)-1-(6-fluoro-2-(2-hydroxyphenyl)quinazolin-4-yl)pyrrolidin-3-ylcarbamate

A mixture of (S)-tetrahydrofuran-3-yl (R)-pyrrolidin-3-ylcarbamate (225mg, 1.12 mmol), 2-(4-chloro-6-fluoroquinazolin-2-yl)phenol (250 mg, 0.86mmol), and triethylamine (0.240 mL, 1.72 mmol) in CH₂Cl₂ (10 mL) wasstirred at room temperature. The reaction was complete in one hour. Thereaction was quenched with water, the aqueous layer was extracted twicewith CH₂Cl₂, and the combined organic extracts were dried over MgSO₄,filtered, and concentrated. Purification via silica gel chromatographyusing 0-10% EtOAc/CH₂Cl₂ gave (S)-tetrahydrofuran-3-yl(R)-1-(6-fluoro-2-(2-hydroxyphenyl)quinazolin-4-yl)pyrrolidin-3-ylcarbamate(250 mg, 66%). LC/MS: m/z 439.5 (M+H)⁺ at 2.40 min (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)). ¹H NMR (400 MHz, DMSO-d6) δ 8.43 (dd,J=7.8, 1.5 Hz, 1H), 7.99 (d, J=2.6 Hz, 1H), 7.87-7.91 (m, 1H), 7.74-7.79(m, 1H), 7.70 (d, J=6.2 Hz, 1H), 7.35-7.39 (m, 1H), 6.91-6.96 (m, 2H),5.15 (s, 1H), 4.21-4.25 (m, 2H), 4.12-4.14 (m, 1H), 4.01-4.06 (m, 1H),3.87-3.89 (m, 1H), 3.65-3.78 (m, 4H), 2.02-2.26 (m, 3H), 1.82-1.89 (m,1H) ppm.

(S)-Tetrahydrofuran-3-yl(R)-1-(6-fluoro-2-(2-hydroxyphenyl)quinazolin-4-yl)pyrrolidin-3-ylcarbamatehydrochloride

To a mixture of (S)-tetrahydrofuran-3-yl(R)-1-(6-fluoro-2-(2-hydroxyphenyl)quinazolin-4-yl)pyrrolidin-3-ylcarbamate(250 mg, 0.57 mmol) and CH₂Cl₂ (25 mL) was added a 2.0 M HCl solution inether (0.285 mL, 0.57 mmol). After the addition of ether (40 mL), thereaction was stirred for 1 h. The resulting solid was filtered and driedto afford (S)-tetrahydrofuran-3-yl(R)-1-(6-fluoro-2-(2-hydroxyphenyl)quinazolin-4-yl)pyrrolidin-3-ylcarbamatehydrochloride. LC/MS: m/z 439.5 (M+H)⁺ at 2.25 min (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)). ¹H NMR (400 MHz, DMSO-d6) δ 8.18 (dd,J=8.1, 1.4 Hz, 1H), 8.00 (d, J=9.6 Hz, 1H), 7.90-7.94 (m, 1H), 7.78-7.83(m, 1H), 7.45-7.49 (m, 1H), 7.00-7.03 (m, 2H), 5.10 (s, 1H), 4.09-4.25(m, 4H), 3.90-3.92 (m, 1H), 3.62-3.75 (m, 4H), 2.22-2.27 (m, 1H),2.03-2.14 (m, 2H), 1.83-1.91 (m, 1H) ppm.

Example 3363-(Trifluoromethyl)-N—((R)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-yl)benzamide

3-(Trifluoromethyl)-N—((R)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-yl)benzamide

2-(4-((R)-3-Aminopyrrolidin-1-yl)-7-methylquinazolin-2-yl)phenol (130mg, 0.406 mmol) was dissolved in 0.7 mL anhydrous CH₂Cl₂ and cooled to0° C. 3-(Trifluoromethyl)benzoyl chloride (42 mg, 0.18 mmol) dissolvedin 0.7 mL of anhydrous CH₂Cl₂ was added dropwise to the mixture followedby triethylamine (53 mg, 74 μL, 0.52 mmol). The reaction was stirred for20 minutes at 0° C. and purified via reverse phase HPLC (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)) to give3-(trifluoromethyl)-N—((R)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-yl)benzamideas the TFA salt. LC/MS: m/z 493.5 (M+H)⁺ at 3.03 min (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)).

Example 337 (R)-Tetrahydrofuran-3-yl(R)-1-(6-fluoro-2-(2-hydroxyphenyl)quinazolin-4-yl)pyrrolidin-3-ylcarbamate

(R)-Tetrahydrofuran-3-yl(R)-1-(6-fluoro-2-(2-hydroxyphenyl)quinazolin-4-yl)pyrrolidin-3-ylcarbamate

To a solution of2-(4-((R)-3-aminopyrrolidin-1-yl)-6-fluoroquinazolin-2-yl)phenol (0.03g, 0.092 mmol) in DMF (1.0 mL) was cooled to −40° C., triethylamine (26μL, 0.184 mmol) was added, followed by the addition of(R)-tetrahydrofuran-3-yl chloroformate (0.014 g, 0.092 mmol). Afterwarming to room temperature, the mixture was filtered, and purified viareverse phase HPLC (10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)) toobtain (R)-tetrahydrofuran-3-yl(R)-1-(6-fluoro-2-(2-hydroxyphenyl)quinazolin-4-yl)pyrrolidin-3-ylcarbamateas the TFA salt. LC/MS: m/z 439.5 (M+H)⁺ at 2.25 min (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)).

Example 338N—((R)-1-(6-Fluoro-2-(2-hydroxyphenyl)quinazolin-4-yl)pyrrolidin-3-yl)-2-(tetrahydro-2H-pyran-4-yl)acetamide

N—((R)-1-(6-Fluoro-2-(2-hydroxyphenyl)quinazolin-4-yl)pyrrolidin-3-yl)-2-(tetrahydro-2H-pyran-4-yl)acetamide

To a solution of2-(4-((R)-3-aminopyrrolidin-1-yl)-6-fluoroquinazolin-2-yl)phenol(0.03 g,0.092 mmol) in DMF (1.0 mL) was added 2-(tetrahydro-2H-pyran-4-yl)aceticacid (0.017 g, 0.12 mmol), followed by the addition of triethylamine(25.6 μL, 0.184 mmol) and HATU (0.045 g, 0.12 mmol). The reaction wasstirred at room temperature for 2 h, filtered, and purified via reversephase HPLC (10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)) to obtainN—((R)-1-(6-fluoro-2-(2-hydroxyphenyl)quinazolin-4-yl)pyrrolidin-3-yl)-2-(tetrahydro-2H-pyran-4-yl)acetamideas the TFA salt. LC/MS: m/z 451.5 (M+H)⁺ at 2.15 min (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)).

Example 339 (Tetrahydro-2H-pyran-2-yl)methyl(R)-1-(6-fluoro-2-(2-hydroxyphenyl)quinazolin-4-yl)pyrrolidin-3-ylcarbamate

(Tetrahydro-2H-pyran-2-yl)methyl(R)-1-(6-fluoro-2-(2-hydroxyphenyl)quinazolin-4-yl)pyrrolidin-3-ylcarbamate

To a solution of2-(4-((R)-3-aminopyrrolidin-1-yl)-7-methylquinazolin-2-yl)phenol (50 mg,0.16 mmol) in DMSO (0.5 mL) at room temperature was added triethylamine(43 μL, 0.31 mmol), followed by the addition of(tetrahydro-2H-pyran-2-yl)methyl 1H-imidazole-1-carboxylate (39 mg, 0.13mmol). The reaction was stirred at room temperature overnight, filtered,and purified via reverse phase HPLC (10%-99% CH₃CN (0.035% TFA)/H₂O(0.05% TFA)) to afford (tetrahydro-2H-pyran-2-yl)methyl(R)-1-(6-fluoro-2-(2-hydroxyphenyl)quinazolin-4-yl)pyrrolidin-3-ylcarbamateas the TFA salt. LC/MS: m/z 467.3 (M+H)⁺ at 3.13 min (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)).

Example 340N—((R)-1-(2-(2-Hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-yl)-2,2,3,3-tetramethylcyclopropanecarboxamide

N—((R)-1-(2-(2-Hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-yl)-2,2,3,3-tetramethylcyclopropanecarboxamide

2-(4-((R)-3-Aminopyrrolidin-1-yl)-6-fluoroquinazolin-2-yl)phenol (50 mg,0.156 mmol) was dissolved in 0.52 mL of anhydrous CH₂Cl₂.2,2,3,3-Tetramethylcyclopropanecarboxylic acid (26.63 mg, 0.18 mmol) wasadded, followed by triethylamine (22.14 mg, 30.49 μL, 0.22 mmol) and BOP(82.93 mg, 0.18 mmol). After stirring the mixture for 30 minutes at roomtemperature, it was filtered, and purified by reverse phase HPLC(10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)) to giveN—((R)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-yl)-2,2,3,3-tetramethylcyclopropanecarboxamideas the TFA salt. LC/MS: m/z 445.4 (M+H)⁺ at 2.95 min (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)).

Example 3414-Fluoro-N—((R)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-yl)benzamide

4-Fluoro-N—((R)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-yl)benzamide

2-(4-((R)-3-Aminopyrrolidin-1-yl)-7-methylquinazolin-2-yl)phenol (50 mg,0.16 mmol) was dissolved in 260 μL of anhydrous CH₂Cl₂ and cooled to 0°C. 4-Fluorobenzoyl chloride (25 mg, 0.15 mmol) dissolved in 260 μL ofanhydrous CH₂Cl₂ was added dropwise to the mixture followed bytriethylamine (19 mg, 26 μL, 0.18 mmol). The reaction was stirred for 15minutes at 0° C. and purified via reverse phase HPLC (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)) to give4-fluoro-N—((R)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-yl)benzamideas the TFA salt. LC/MS: m/z 443.4 (M+H)⁺ at 2.73 min (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)).

Example 3423-(Dimethylamino)-N—((R)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-yl)benzamide

3-(Dimethylamino)-N—((R)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-yl)benzamide

2-(4-((R)-3-Aminopyrrolidin-1-yl)-7-methylquinazolin-2-yl)phenol (50 mg,0.16 mmol) was dissolved in 260 μL of anhydrous CH₂Cl₂ and cooled to 0°C. 3-(Dimethylamino)benzoyl chloride hydrochloride (34 mg, 0.15 mmol)dissolved in 260 μL of anhydrous CH₂Cl₂ was added dropwise to themixture followed by triethylamine (32 mg, 44 μL, 0.31 mmol). Thereaction was stirred for 1.5 hour at 0° C. and purified via reversephase HPLC (10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)) to give3-(dimethylamino)-N—((R)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-yl)benzamideas the TFA salt. LC/MS: m/z 468.4 (M+H)⁺ at 2.39 min (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)).

Example 3432-(Trifluoromethyl)-N—((R)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-yl)benzamide

2-(Trifluoromethyl)-N—((R)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-yl)benzamide

2-(4-((R)-3-Aminopyrrolidin-1-yl)-7-methylquinazolin-2-yl)phenol (50 mg,0.16 mmol) was dissolved in 260 μL of anhydrous CH₂Cl₂ and cooled to 0°C. 2-(Trifluoromethyl)benzoyl chloride (39 mg, 0.18 mmol) dissolved in260 μL of anhydrous CH₂Cl₂ was added dropwise to the mixture followed bytriethylamine (21 mg, 28 μL, 0.20 mmol). The reaction was stirred for 20minutes at 0° C. and purified via reverse phase HPLC (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)) to give2-(trifluoromethyl)-N—((R)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-yl)benzamideas the TFA salt. LC/MS: m/z 493.4 (M+H)⁺ at 2.76 min (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)).

Example 3442-Fluoro-N—((R)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-yl)benzamide

2-Fluoro-N—((R)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-yl)benzamide

2-(4-((R)-3-Aminopyrrolidin-1-yl)-7-methylquinazolin-2-yl)phenol (50.6mg, 0.158 mmol) was dissolved in 260 μL of anhydrous CH₂Cl₂ and cooledto 0° C. 2-Fluorobenzoyl chloride (27 mg, 0.17 mmol) dissolved in 260 μLof anhydrous CH₂Cl₂ was added dropwise to the mixture followed bytriethylamine (21 mg, 28 μL, 0.20 mmol). The reaction was stirred for 15minutes at 0° C. and purified via reverse phase HPLC (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)) to give2-fluoro-N—((R)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-yl)benzamideas the TFA salt. LC/MS: m/z 443.4 (M+H)⁺ at 2.69 min (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)).

Example 345 (S)-Tetrahydrofuran-3-yl(R)-1-(2-(2-fluoro-6-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-ylcarbamate

tert-Butyl(R)-1-(2-(2-fluoro-6-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-ylcarbamate

A solution of tert-butyl (R)-pyrrolidin-3-ylcarbamate (368 mg, 1.97mmol) and triethylamine (0.46 mL, 3.28 mmol) in CH₂Cl₂ was rapidly addedto a stirring solution of2-(4-chloro-7-methylquinazolin-2-yl)-3-fluorophenol (475 mg, 1.65 mmol)in 15 mL CH₂Cl₂ at 0° C. under an N₂ atmosphere. The reaction wasstirred for 1 h before it was quenched with water, and the aqueous layerwas extracted twice with CH₂Cl₂. The combined organic extracts weredried over MgSO₄, filtered, and concentrated. Purification via silicagel chromatography using 0-10% EtOAc/CH₂Cl₂ yielded tert-butyl(R)-1-(2-(2-fluoro-6-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-ylcarbamate.LC/MS: m/z 439.5 (M+H)⁺ at 2.42 min (10%-99% CH₃CN (0.035% TFA)/H₂O(0.05% TFA)).

2-(4-((R)-3-Aminopyrrolidin-1-yl)-7-methylquinazolin-2-yl)-3-fluorophenol

To a solution of tert-butyl(R)-1-(2-(2-fluoro-6-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-ylcarbamate(500 mg, 1.14 mmol) in CH₂Cl₂ (15 mL) was added TFA (5 mL). The mixturewas stirred for 1 h and then neutralized with a 1 M NaOH solution, andthe aqueous layer was extracted twice with CH₂Cl₂. The combined organiclayers were dried over MgSO₄, filtered, and concentrated. Purificationvia silica gel chromatography using 3-20% EtOAc/CH₂Cl₂ gave2-(4-((R)-3-aminopyrrolidin-1-yl)-7-methylquinazolin-2-yl)-3-fluorophenol.LC/MS: m/z 339.5 (M+H)⁺ at 0.56 min (10%-99% CH₃CN (0.035% TFA)/H₂O(0.05% TFA)).

(S)-Tetrahydrofuran-3-yl(R)-1-(2-(2-fluoro-6-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-ylcarbamate

Method A

To a stirred solution of2-(4-((R)-3-aminopyrrolidin-1-yl)-7-methylquinazolin-2-yl)-3-fluorophenol(40 mg, 0.12 mmol) in 800 μL of anhydrous DMF cooled to 0° C. was added(S)-tetrahydrofuran-3-yl chloroformate (20 mg, 19 μL, 0.13 mmol)dropwise, followed by the addition of triethylamine (24 mg, 33 μL, 0.23mmol). The reaction was warmed to room temperature and stirredovernight, and the product purified via reverse phase HPLC (10%-99%CH₃CN (0.035% TFA)/H₂O (0.05% TFA)) to give (S)-tetrahydrofuran-3-yl(R)-1-(2-(2-fluoro-6-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-ylcarbamateas the TFA salt. LC/MS: m/z 453.3 (M+H)⁺ at 2.05 min (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)).

Method B

At room temperature, N-ethyl-N-isopropylpropan-2-amine (155 mL, 0.88mmol) was added to a solution of2-(4-((R)-3-aminopyrrolidin-1-yl)-7-methylquinazolin-2-yl)-3-fluorophenol(150 mg, 0.40 mmol) in THF. The mixture was cooled in an ice bath, and(S)-tetrahydrofuran-3-yl chloroformate (63 mg, 0.42 mmol) was addedslowly over a period of 10 minutes. After warming to room temperature,the reaction was quenched with water and extracted twice with CH₂Cl₂.The combined organic layers were dried over MgSO₄, filtered, andconcentrated. Purification via silica gel chromatography using 0-10%EtOAc in CH₂Cl₂/hexanes (1:1) gave (S)-tetrahydrofuran-3-yl(R)-1-(2-(2-fluoro-6-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-ylcarbamate(160 mg, 84%). LC/MS: m/z 453.3 (M+H)⁺ at 2.12 min (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)). ¹H NMR (400 MHz, DMSO-d6) δ 8.18 (d,J=8.6 Hz, 1H), 7.70 (d, J=6.3 Hz, 1H), 7.58 (s, 1H), 7.29-7.38 (m, 2H),6.76 (d, J=8.3 Hz, 1H), 6.67-6.72 (m, 1H), 5.14 (s, 1H), 4.23-4.24 (m,1H), 3.99-4.13 (m, 3H), 3.64-3.85 (m, 5H), 2.50 (s, 3H), 2.07-2.22 (m,2H), 2.00-2.03 (m, 1H), 1.85-1.90 (m, 1H) ppm.

(S)-Tetrahydrofuran-3-yl(R)-1-(2-(2-fluoro-6-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-ylcarbamatehydrochloride

To a solution of (S)-tetrahydrofuran-3-yl(R)-1-(2-(2-fluoro-6-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-ylcarbamate(160 mg, 0.35 mmol) in 2 mL CH₂Cl₂ was added 2 M HCL solution in ether(0.176 mL, 0.35 mmol) resulting in precipitation of a solid. After theaddition of 10 mL ether, the reaction was stirred for 30 minutes,filtered and the resulting solid was dried to obtain(S)-tetrahydrofuran-3-yl(R)-1-(2-(2-fluoro-6-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-ylcarbamatehydrochloride (130 mg, 76%)). LC/MS: m/z 453.3 (M+H)⁺ at 2.13 min(10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)). ¹H NMR (400 MHz, DMSO-d6)δ 8.29 (s, 1H), 7.57 (s, 2H), 7.43-7.49 (m, 1H), 6.83-6.89 (m, 2H), 5.08(s, 1H), 4.23-4.42 (m, 4H), 3.62-3.73 (m, 5H), 2.24-2.34 (m, 1H),2.04-2.11 (m, 2H), 1.86-1.92 (m, 1H) ppm.

Example 346N—((R)-1-(2-(2-Fluoro-6-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-yl)cyclopropanecarboxamide

N—((R)-1-(2-(2-Fluoro-6-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-yl)cyclopropanecarboxamide

Method A

To a stirred solution of2-(4-((R)-3-aminopyrrolidin-1-yl)-7-methylquinazolin-2-yl)-3-fluorophenol(40 mg, 0.12 mmol) in 800 μL of anhydrous DMF at 0° C. was addedcyclopropanecarboxylic acid (II mg, 0.13 mmol), followed by the additionof triethylamine (24 mg, 33 μL, 0.24 mmol) and HATU (60 mg, 0.16 mmol).The mixture was allowed to warm to room temperature and was stirredovernight. Filtration and purification via reverse phase HPLC (10%-99%CH₃CN (0.035% TFA)/H₂O (0.05% TFA)) gaveN—((R)-1-(2-(2-fluoro-6-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-yl)cyclopropanecarboxamideas the TFA salt. LC/MS: m/z 407.5 (M+H)⁺ at 2.2 min (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)).

Method B

To a solution of2-(4-((R)-3-aminopyrrolidin-1-yl)-7-methylquinazolin-2-yl)-3-fluorophenol(100 mg, 0.295 mmol) in 10 mL DMF, at −20° C., was addedcyclopropanecarboxylic acid (23 μL, 0.30 mmol), followed by the additionof triethylamine (82 μL, 0.59 mmol) and a solution of HATU (124 mg, 0.32mmol) in 4 mL DMF. The mixture was warmed to room temperature andstirred for 1 h. Cold water was added to the reaction mixture whichresulted in the formation of a precipitate which was collected byfiltration and dissolved in CH₂Cl₂. The solution was then dried overMgSO₄, filtered, and concentrated to affordN—((R)-1-(2-(2-fluoro-6-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-yl)cyclopropanecarboxamide(80 mg, 66%) LC/MS: m/z 407.5 (M+H)⁺ at 2.08 min (10%-99% CH₃CN (0.035%TFA)/H₂O (0.05% TFA)).

N—((R)-1-(2-(2-Fluoro-6-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-yl)cyclopropanecarboxamidehydrochloride

A 2 M HCl solution in ether (0.16 mL, 0.32 mmol) was added to a solutionofN—((R)-1-(2-(2-fluoro-6-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-yl)cyclopropanecarboxamide(133 mg, 0.32 mmol) in CH₂Cl₂ (4 mL) under an N₂ atmosphere. Additionalether was then added (15 mL) and the reaction mixture was stirred for anhour. The formed precipitate was then filtered and dried to affordN—((R)-1-(2-(2-fluoro-6-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-yl)cyclopropanecarboxamidehydrochloride (135 mg, 95%). LC/MS: m/z 407.5 (M+H)⁺ at 2.07 min(10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)). ¹H NMR (400 MHz, DMSO-d6)δ 8.32 (d, J=7.6 Hz, 1H), 7.56-7.58 (m, 2H), 7.43-7.49 (m, 1H),6.83-6.88 (m, 2H), 3.94-4.41 (m, 5H), 2.52 (s, 3H), 2.25-2.36 (m, 1H),1.91-2.13 (m, 1H), 1.47-1.54 (m, 1H), 0.63-0.69 (m, 4H) ppm.

Example 347N—((R)-1-(6-Fluoro-2-(2-hydroxyphenyl)quinazolin-4-yl)pyrrolidin-3-yl)isonicotinamide

N—((R)-1-(6-Fluoro-2-(2-hydroxyphenyl)quinazolin-4-yl)pyrrolidin-3-yl)isonicotinamide

To a solution of2-(4-((R)-3-aminopyrrolidin-1-yl)-6-fluoroquinazolin-2-yl)phenol (0.03g, 0.09 mmol) in DMF (1.0 mL) was added isonicotinic acid (0.015 g, 0.12mmol), followed by the addition of triethylamine (25 μL, 0.18 mmol) andHATU (0.045 g, 0.12 mmol). The reaction was stirred at room temperaturefor 2 h, filtered, and purified using reverse phase HPLC (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)) to obtainN—((R)-1-(6-fluoro-2-(2-hydroxyphenyl)quinazolin-4-yl)pyrrolidin-3-yl)isonicotinamideas the TFA salt. LC/MS: m/z 430.5 (M+H)⁺ at 1.95 min (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)).

Example 348N—((R)-1-(6-Fluoro-2-(2-hydroxyphenyl)quinazolin-4-yl)pyrrolidin-3-yl)picolinamide

N—((R)-1-(6-Fluoro-2-(2-hydroxyphenyl)quinazolin-4-yl)pyrrolidin-3-yl)picolinamide

To a solution of2-(4-((R)-3-aminopyrrolidin-1-yl)-6-fluoroquinazolin-2-yl)phenol (0.03g, 0.09 mmol) in DMF (1.0 mL) was added picolinic acid (0.015 g, 0.12mmol), followed by the addition of triethylamine (25 μL, 0.18 mmol) andHATU (0.045 g, 0.12 mmol). The reaction was stirred at room temperaturefor 2 h, filtered, and purified using reverse phase HPLC (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)) to obtainN—((R)-1-(6-fluoro-2-(2-hydroxyphenyl)quinazolin-4-yl)pyrrolidin-3-yl)picolinamideas the TFA salt. LC/MS: m/z 430.5 (M+H)⁺ at 2.43 min (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)).

Example 349N—((R)-1-(6-Fluoro-2-(2-hydroxyphenyl)quinazolin-4-yl)pyrrolidin-3-yl)nicotinamide

N—((R)-1-(6-Fluoro-2-(2-hydroxyphenyl)quinazolin-4-yl)pyrrolidin-3-yl)nicotinamide

To a solution of2-(4-((R)-3-aminopyrrolidin-1-yl)-6-fluoroquinazolin-2-yl)phenol (0.03g, 0.09 mmol) in DMF (1.0 mL) was added nicotinic acid (0.015 g, 0.12mmol), followed by the addition of triethylamine (25 μL, 0.18 mmol) andHATU (0.045 g, 0.12 mmol). The reaction was stirred at room temperaturefor 2 h, filtered, and purified using reverse phase HPLC (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)) to obtainN—((R)-1-(6-fluoro-2-(2-hydroxyphenyl)quinazolin-4-yl)pyrrolidin-3-yl)nicotinamideas the TFA salt. LC/MS: m/z 430.5 (M+H)⁺ at 1.98 min (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)).

Example 350N—((R)-1-(2-(2-Fluoro-6-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-yl)isonicotinamide

N—((R)-1-(2-(2-Fluoro-6-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-yl)isonicotinamide

To a solution of2-(4-((R)-3-aminopyrrolidin-1-yl)-7-methylquinazolin-2-yl)-3-fluorophenol(0.03 g, 0.09 mmol) in DMF (0.5 mL) was added isonicotinic acid (0.014g, 0.12 mmol), followed by the addition of triethylamine (25 μL, 0.18mmol) and HATU (0.045 g, 0.12 mmol). The reaction was stirred at roomtemperature for 2 h, filtered, and purified via reverse phase HPLC(10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)) to obtainN—((R)-1-(2-(2-fluoro-6-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-yl)isonicotinamideas the TFA salt. LC/MS: m/z 444.5 (M+H)⁺ at 1.85 min (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)).

Example 351N—((R)-1-(2-(2-Fluoro-6-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-yl)picolinamide

N—((R)-1-(2-(2-Fluoro-6-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-yl)picolinamide

To a solution of2-(4-((R)-3-aminopyrrolidin-1-yl)-7-methylquinazolin-2-yl)-3-fluorophenol(0.03 g, 0.09 mmol) in DMF (1.0 mL) was added picolinic acid (0.014 g,0.12 mmol), followed by the addition of triethylamine (25 μL, 0.18 mmol)and HATU (0.045 g, 0.12 mmol). The reaction was stirred at roomtemperature for 2 h, filtered, and purified via reverse phase HPLC(10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)) to obtainN—((R)-1-(2-(2-fluoro-6-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-yl)picolinamideas the TFA salt. LC/MS: m/z 444.5 (M+H)⁺ at 2.24 min (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)).

Example 352N—((R)-1-(2-(2-Fluoro-6-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-yl)nicotinamide

N—((R)-1-(2-(2-Fluoro-6-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-yl)nicotinamide

To a solution of2-(4-((R)-3-aminopyrrolidin-1-yl)-7-methylquinazolin-2-yl)-3-fluorophenol(0.03 g, 0.09 mmol) in DMF (1.0 mL) was added nicotinic acid (0.014 g,0.12 mmol), followed by the addition of triethylamine (25 μL, 0.18 mmol)and HATU (0.045 g, 0.12 mmol). The reaction was stirred at roomtemperature for 2 h, filtered, and purified via reverse phase HPLC(10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)) to obtainN—((R)-1-(2-(2-fluoro-6-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-yl)nicotinamideas the TFA salt. LC/MS: m/z 444.5 (M+H)⁺ at 1.89 min (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)).

Example 353N—((R)-1-(2-(2-Hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-yl)isonicotinamide

N—((R)-1-(2-(2-Hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-yl)isonicotinamide

To a solution of2-(4-((R)-3-aminopyrrolidin-1-yl)-7-methylquinazolin-2-yl)phenol (0.03g, 0.09 mmol) in DMF (1.0 mL) was added isonicotinic acid (0.015 g, 0.12mmol), followed by the addition of triethylamine (25 μL, 0.18 mmol) andHATU (0.045 g, 0.12 mmol). The reaction was stirred at room temperaturefor 2 h, filtered, and purified via reverse phase HPLC (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)) to obtainN—((R)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-yl)isonicotinamideas the TFA salt. LC/MS: m/z 426.1 (M+H)⁺ at 1.93 min (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)).

Example 354N—((R)-1-(2-(2-Hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-yl)picolinamide

N—((R)-1-(2-(2-Hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-yl)picolinamide

To a solution of2-(4-((R)-3-aminopyrrolidin-1-yl)-7-methylquinazolin-2-yl)phenol (0.03g, 0.09 mmol) in DMF (1.0 mL) was added picolinic acid (0.015 g, 0.12mmol), followed by the addition of triethylamine (25 μL, 0.18 mmol) andHATU (0.045 g, 0.12 mmol). The reaction was stirred at room temperaturefor 2 h, filtered, and purified via reverse phase HPLC (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)) to obtainN—((R)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-yl)picolinamideas the TFA salt. LC/MS: m/z 426.1 (M+H)⁺ at 2.33 min (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)).

Example 355 (R)-Tetrahydrofuran-3-yl((S)-1-(6-fluoro-2-(2-hydroxyphenyl)quinazolin-4-yl)pyrrolidin-3-yl)methylcarbamate

Benzyl ((S)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)methylcarbamate

To a stirred solution of((S)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)methylcarbamate (1.5 g, 4.48mmol) in CH₂Cl₂ (20 mL) was slowly added TFA (5 mL). The reaction wasstirred for 2 h. After removing the solvents under reduced pressure, themixture was neutralized with a 1 M NaOH solution and extracted twicewith CH₂Cl₂. The combined organic layers were dried over MgSO₄,filtered, and concentrated to afford benzyl ((R)-pyrrolidin-3-yl)methylcarbamate (800 mg, 76%). LC/MS: m/z 235.3 (M+H)⁺at 1.22 min (10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)).

Benzyl ((R)-pyrrolidin-3-yl)methylcarbamate

To a stirred solution of((S)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)methylcarbamate (1.5 g, 4.48mmol) in CH₂Cl₂ (20 mL) was slowly added TFA (5 mL). The reaction wasstirred for 2 h. After removing the solvents under reduced pressure, themixture was neutralized with a 1 M NaOH solution and extracted twicewith CH₂Cl₂. The combined organic layers were dried over MgSO₄,filtered, and concentrated to afford benzyl ((R)-pyrrolidin-3-yl)methylcarbamate (800 mg, 76%). LC/MS: m/z 335.3 (M+H)⁺at 1.22 min (10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)).

Benzyl((S)-1-(6-fluoro-2-(2-hydroxyphenyl)quinazolin-4-yl)pyrrolidin-3-yl)methylcarbamate

A solution of triethylamine (507 μL, 3.64 mmol) and benzyl((R)-pyrrolidin-3-yl)methylcarbamate (0.47 g, 2 mmol) in CH₂Cl₂ wasadded dropwise to a solution of2-(4-chloro-6-fluoroquinazolin-2-yl)phenol (0.5 g, 1.82 mmol) in CH₂Cl₂(20 mL). The reaction was stirred at room temperature for 3 h. Afterquenching the reaction with water, the aqueous phase was extracted twicewith CH₂Cl₂. The combined organic layers were dried over MgSO₄,filtered, and concentrated. Purification via silica gel chromatographyusing 5-10% EtOAc in CH₂Cl₂ yielded benzyl((S)-1-(6-fluoro-2-(2-hydroxyphenyl)quinazolin-4-yl)pyrrolidin-3-yl)methylcarbamate.LC/MS: m/z 473.1 (M+H)⁺ at 2.91 min (10%-99% CH₃CN (0.035% TFA)/H₂O(0.05% TFA)).

2-(4-((S)-3-(Aminomethyl)pyrrolidin-1-yl)-6-fluoroquinazolin-2-yl)phenol

Under an N₂ atmosphere, a mixture of benzyl((S)-1-(6-fluoro-2-(2-hydroxyphenyl)quinazolin-4-yl)pyrrolidin-3-yl)methylcarbamate(0.770 g, 1.6 mmol) and MeOH (5 mL) was added to Pd/C (77 mg, 10% weightPd on carbon) weighed into a 100 mL flask. After the atmosphere in theflask was evacuated and purged with N₂ three times, the reaction mixturewas vigorously stirred under an H₂ atmosphere at ambient pressureovernight and then filtered through a pad of Celite, concentrated, anddried to obtain2-(4-((S)-3-(aminomethyl)pyrrolidin-1-yl)-6-fluoroquinazolin-2-yl)phenol(0.45 g, 81%). LC/MS: m/z 459.5 (M+H)⁺ at 2.81 min (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)).

(R)-Tetrahydrofuran-3-yl((S)-1-(6-fluoro-2-(2-hydroxyphenyl)quinazolin-4-yl)pyrrolidin-3-yl)methylcarbamate

To a solution of2-(4-((S)-3-(aminomethyl)pyrrolidin-1-yl)-6-fluoroquinazolin-2-yl)phenol(0.03 g, 0.09 mmol) in DMF (1.0 mL) at −60° C. (external temperature)was added triethylamine (25 mL, 0.18 mmol) and (R)-tetrahydrofuran-3-ylchloroformate (13 mg, 0.09 mmol). The reaction was warmed to roomtemperature, filtered, and purified via reverse phase HPLC (10%-99%CH₃CN (0.035% TFA)/H₂O (0.05% TFA)) to afford (R)-tetrahydrofuran-3-yl((S)-1-(6-fluoro-2-(2-hydroxyphenyl)quinazolin-4-yl)pyrrolidin-3-yl)methylcarbamateas the TFA salt. LC/MS: m/z 453.3 (M+H)⁺ at 2.29 min (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)).

Example 356 (S)-Tetrahydrofuran-3-yl((S)-1-(6-fluoro-2-(2-hydroxyphenyl)quinazolin-4-yl)pyrrolidin-3-yl)methylcarbamate

(S)-Tetrahydrofuran-3-yl((S)-1-(6-fluoro-2-(2-hydroxyphenyl)quinazolin-4-yl)pyrrolidin-3-yl)methylcarbamate

To a solution of2-(4-((S)-3-(aminomethyl)pyrrolidin-1-yl)-6-fluoroquinazolin-2-yl)phenol(0.03 g, 0.09 mmol) in DMF (1.0 mL) at −60° C. (external temperature)was added triethylamine (25 mL, 0.18 mmol) and (S)-tetrahydrofuran-3-ylchloroformate (13 mg, 0.09 mmol). The reaction was warmed to roomtemperature, filtered, and purified via reverse phase HPLC (10%-99%CH₃CN (0.035% TFA)/H₂O (0.05% TFA)) to afford (S)-tetrahydrofuran-3-yl((S)-1-(6-fluoro-2-(2-hydroxyphenyl)quinazolin-4-yl)pyrrolidin-3-yl)methylcarbamateas the TFA salt. LC/MS: m/z 453.3 (M+H)⁺ at 2.29 min (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)).

Example 357N—(((S)-1-(6-Fluoro-2-(2-hydroxyphenyl)quinazolin-4-yl)pyrrolidin-3-yl)methyl)cyclopropanecarboxamide

N—(((S)-1-(6-Fluoro-2-(2-hydroxyphenyl)quinazolin-4-yl)pyrrolidin-3-yl)methyl)cyclopropanecarboxamide

To a solution of2-(4-((S)-3-(aminomethyl)pyrrolidin-1-yl)-6-fluoroquinazolin-2-yl)phenol(0.03 g, 0.09 mmol) and cyclopropanecarboxylic acid (10 mg, 0.12 mmol)in DMF (1.0 mL) was added triethylamine (25 μL, 0.18 mmol) followed bythe addition of HATU (45 mg, 0.117 mmol). The reaction was stirred atroom temperature for 2 h, filtered, and purified via reverse phase HPLC(10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)) to obtainN—(((S)-1-(6-fluoro-2-(2-hydroxyphenyl)quinazolin-4-yl)pyrrolidin-3-yl)methyl)cyclopropanecarboxamideas the TFA salt. LC/MS: m/z 407.3 (M+H)⁺ at 2.26 min (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)).

Example 358N—((R)-1-(6-Fluoro-2-(2-hydroxyphenyl)quinazolin-4-yl)pyrrolidin-3-yl)-2-(4-fluorophenyl)-2-hydroxyacetamide

N—((R)-1-(6-Fluoro-2-(2-hydroxyphenyl)quinazolin-4-yl)pyrrolidin-3-yl)-2-(4-fluorophenyl)-2-hydroxyacetamide

To a solution of2-(4-((R)-3-aminopyrrolidin-1-yl)-6-fluoroquinazolin-2-yl)phenol (0.03g, 0.09 mmol) in DMF (1.0 mL) was added2-(4-fluorophenyl)-2-hydroxyacetic acid (20 mg, 0.12 mmol), followed bythe addition of triethylamine (25 μL, 0.18 mmol) and HATU (0.045 g, 0.12mmol). The reaction was stirred at room temperature for 2 h, filtered,and purified using reverse phase HPLC (10%-99% CH₃CN (0.035% TFA)/H₂O(0.05% TFA)) to obtainN—((R)-(6-fluoro-2-(2-hydroxyphenyl)quinazolin-4-yl)pyrrolidin-3-yl)-2-(4-fluorophenyl)-2-hydroxyacetamideas the TFA salt. LC/MS: m/z 477.3 (M+H)⁺ at 2.80 min (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)).

Example 359N—((R)-1-(2-(2-Fluoro-6-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-yl)-2-(4-fluorophenyl)-2-hydroxyacetamide

N—((R)-1-(2-(2-(2-Fluoro-6-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-yl)-2-(4-fluorophenyl)-2-hydroxyacetamide

To a solution of2-(4-((R)-3-aminopyrrolidin-1-yl)-7-methylquinazolin-2-yl)-3-fluorophenol(0.03 g, 0.09 mmol) in DMF (1.0 mL) was added2-(4-fluorophenyl)-2-hydroxyacetic acid (0.020 g, 0.12 mmol), followedby the addition of triethylamine (25.6 μL, 0.184 mmol) and HATU (0.045g, 0.12 mmol). The reaction was stirred at room temperature for 2 h,filtered, and purified using reverse phase HPLC (10%-99% CH₃CN (0.035%TFA)/H₂O (0.05% TFA)) to obtainN—((R)-1-(2-(2-fluoro-6-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-yl)-2-(4-fluorophenyl)-2-hydroxyacetamideas the TFA salt. LC/MS: m/z 4491.3 (M+H)⁺ at 2.46 min (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)).

Example 3602-(4-Fluorophenyl)-2-hydroxy-N—((R)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-yl)acetamide

2-(4-Fluorophenyl)-2-hydroxy-N—((R)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-yl)acetamide

To a solution of2-(4-((R)-3-aminopyrrolidin-1-yl)-7-methylquinazolin-2-yl)phenol (0.03g, 0.09 mmol) in DMF (1.0 mL) was added2-(4-fluorophenyl)-2-hydroxyacetic acid (0.02 g, 0.12 mmol), followed bythe addition of triethylamine (25 μL, 0.18 mmol) and HATU (0.045 g, 0.12mmol). The reaction was stirred at room temperature for 2 h, filtered,and purified using reverse phase HPLC (10%-99% CH₃CN (0.035% TFA)/H₂O(0.05% TFA)) to obtain2-(4-fluorophenyl)-2-hydroxy-N—((R)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-yl)acetamideas the TFA salt. LC/MS: m/z 473.1 (M+H)⁺ at 2.32 min (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)).

Example 361(2R)-2-Hydroxy-N—((R)-1-(2-(2-Hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-yl)-4,4-dimethylpentanamide

(2R)-2-Hydroxy-N—((R)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-yl)-4,4-dimethylpentanamide

To a stirred solution of2-(4-((R)-3-aminopyrrolidin-1-yl)-7-methylquinazolin-2-yl)phenol (50 mg,0.16 mmol) in 1 mL of DMF cooled at 0° C. was added(R)-2-hydroxy-4,4-dimethylpentanoic acid (27.3 mg, 0.187 mmol), followedby the addition of triethylamine (32 mg, 44 μL, 0.31 mmol), then HATU(71.1 mg, 0.187 mmol). The reaction was stirred at 0° C. for 10 minutes,warmed to room temperature, filtered, and purified via reverse phaseHPLC (10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)) to afford(2R)-2-hydroxy-N—((R)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-yl)-4,4-dimethylpentanamideas the TFA salt. LC/MS: m/z 449.3 (M+H)⁺ at 2.4 min (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)).

Example 362 Benzyl((R)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-yl)methylcarbamate

Benzyl((R)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-yl)methylcarbamate

A mixture of benzyl((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)methylcarbamate (0.20 g,0.60 mmol) and 4 M HCl (10 mL) in dioxane was stirred at roomtemperature for 3 h. After evaporating the solvent under reducedpressure, the solid was triturated with Et₂O, dried under vacuum, andtaken up in CH₂Cl₂ (10 mL). 2-(4-Chloro-7-methylquinazolin-2-yl)phenol(0.16 g, 0.60 mmol) was added to this solution, followed by the additionof triethylamine (0.25 mL, 1.8 mmol). The reaction mixture was stirredat room temperature overnight, then diluted with CH₂Cl₂ and washed withwater. The combined organic layers were dried over Na₂SO₄, filtered, andconcentrated. Purification via silica gel chromatography using 0-40%EtOAc in hexanes gave benzyl((R)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-yl)methylcarbamateas a colorless oil (0.19 g, 68% yield). LC/MS: m/z 469.1 (M+H)⁺ at 2.58min (10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)).

Example 363 Benzyl((S)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-yl)methylcarbamate

Benzyl((S)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-yl)methylcarbamate

A mixture of benzyl((S)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)methylcarbamate (0.20 g,0.60 mmol) and 4 M HCl in dioxane (10 mL) was stirred for 3 h at roomtemperature. After evaporating the solvent under reduced pressure, thesolid was triturated with Et₂O, dried under vacuum, and taken up inCH₂Cl₂ (10 mL). 2-(4-Chloro-7-methylquinazolin-2-yl)phenol (0.16 g, 0.60mmol) was added to this solution, followed by the addition oftriethylamine (0.25 mL, 1.8 mmol). The reaction mixture was stirred atroom temperature overnight, then diluted with CH₂Cl₂ and washed withwater. The combined organic layers were dried over Na₂SO₄, filtered, andconcentrated. Purification via silica gel chromatography using 0-40%EtOAc in hexanes gave benzyl((S)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-yl)methylcarbamateas a colorless oil (0.19 g, 68% yield). LC/MS: m/z 469.1 (M+H)⁺ at 2.58min (10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)).

Example 364 Ethyl((S)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-yl)methylcarbamate

Ethyl((S)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-yl)methylcarbamate

A solution of2-(4-((S)-3-(aminomethyl)pyrrolidin-1-yl)-7-methylquinazolin-2-yl)phenol(25 mg, 0.075 mmol) in CH₂Cl₂ (1.0 mL) was cooled in an ice bath. Tothis mixture was added ethyl chloroformate (7.8 μL, 0.082 mmol),followed by triethylamine (21 μL, 0.15 mmol). After removing the icebath, the reaction was stirred for 3 h at room temperature. Purificationvia preparative reverse phase HPLC (10%-99% CH₃CN (0.035% TFA)/H₂O(0.05% TFA)) gave ethyl((S)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-yl)methylcarbamateas the TFA salt. LC/MS: m/z 407.1 (M+H)⁺ at 2.29 min (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)).

Example 365 Isobutyl((S)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-yl)methylcarbamate

Isobutyl((S)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-yl)methylcarbamate

Method A

A solution of2-(4-((S)-3-(aminomethyl)pyrrolidin-1-yl)-7-methylquinazolin-2-yl)phenol(25 mg, 0.075 mmol) in CH₂Cl₂ (1.0 mL) was cooled in an ice bath. Tothis mixture was added isobutyl chloroformate (11 μL, 0.082 mmol),followed by the addition of triethylamine (21 μL, 0.15 mmol). Afterremoving the ice bath, the reaction was stirred for 3 h at roomtemperature. Purification via preparative reverse phase HPLC (10%-99%CH₃CN (0.035% TFA)/H₂O (0.05% TFA)) gave isobutyl((S)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-yl)methylcarbamateas the TFA salt. LC/MS: m/z 435.3 (M+H)⁺ at 2.55 min (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)).

Method B

A mixture of2-(4-((S)-3-(aminomethyl)pyrrolidin-1-yl)-7-methylquinazolin-2-yl)phenol(200 mg, 0.6 mmol), THF (6.0 mL), and CH₂Cl₂ was stirred under an N₂atmosphere. Triethylamine (0.166 mL, 1.2 mmol) was added, and thereaction was cooled in an ice bath. To this was added 1 M isobutylchloroformate solution (78 μL in 600 μL THF, 0.6 mmol). After allowingthe reaction mixture to warm to room temperature, CH₂Cl₂ was added, andthe organic solution washed twice with water, then dried over Na₂SO₄,filtered, and concentrated. Purification via silica gel chromatographyusing 0-20% EtOAc in CH₂Cl₂/hexanes (1:1) gave isobutyl((S)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-yl)methylcarbamate(183 mg, 70%). LC/MS: m/z 435.5 (M+H)⁺ at 2.63 min (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)). LC/MS: m/z 435 (M+H)⁺ at 2.63 min(10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)). ¹H NMR (400 MHz, DMSO-d6)δ 8.43 (dd, J=8.2, 1.8 Hz, 1H), 8.22 (d, J=8.7 Hz, 1H), 7.58 (s, 1H),7.42-7.31 (m, 3H), 6.93-6.89 (m, 2H), 4.17-3.91 (m, 3H), 3.80-3.69 (m,3H), 3.34-3.30 (m, 1H), 3.21-3.07 (m, 2H), 2.49 (s, 3H), 2.16-2.08 (m,1H), 1.88-1.74 (m, 2H), 0.88 (d, J=6.7 Hz, 6H) ppm.

Isobutyl((S)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-yl)methylcarbamatehydrochloride

A solution of isobutyl((S)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-yl)methylcarbamate(183 mg, 0.42 mmol) in CH₂Cl₂ (1.5 mL) was stirred under an N₂atmosphere. A 1.0 M HCl solution in ether (0.42 ml, 0.42 mmol) was addeddropwise to this solution. After 10 minutes, 5 mL ether was added, and aprecipitate formed which was filtered and dried to obtain isobutyl((S)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-yl)methylcarbamatehydrochloride (169 mg, 85%). LC/MS: m/z 435.5 (M+H)+at 2.64 min (10%-99%CH₃CN (0.035% TFA)/H₂O (0.05% TFA)). ¹H NMR (400 MHz, DMSO-d6) δ 8.31(d, J=8.7 Hz, 1H), 8.24 (d, J=6.8 Hz, 1H), 7.80 (s, 1H), 7.53-7.45 (m,2H), 7.41-7.38 (m, 1H), 7.12 (d, J=8.2 Hz, 1H), 7.05-7.02 (m, 1H),4.36-3.85 (m, 5H), 3.77-3.70 (m, 2H), 3.22-3.06 (m, 2H), 2.54 (s, 3H),2.18-2.13 (m, 1H), 1.87-1.77 (m, 2H), 0.87 (d, J=6.7 Hz, 6H) ppm.

Example 366 2-Methoxyethyl((S)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-yl)methylcarbamate

2-Methoxyethyl((S)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-yl)methylcarbamate

Method A

A solution of2-(4-((S)-3-(aminomethyl)pyrrolidin-1-yl)-7-methylquinazolin-2-yl)phenol(25 mg, 0.075 mmol) in anhydrous CH₂Cl₂ was cooled in an ice bath. Then2-methoxyethyl chloroformate (8.6 μL, 0.075 mmol) was added, followed bythe addition of triethylamine (16 μL, 0.11 mmol). After removing the icebath, the reaction was stirred at room temperature for 4 h. Water andsaturated aqueous NaHCO₃ solution were added, and the reaction mixturewas stirred at room temperature overnight. After separation of theaqueous and organic layers, the organic phase was dried over Na₂SO₄,filtered, and concentrated. Purification via preparative reverse phaseHPLC (10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)) gave 2-methoxyethyl((S)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-yl)methylcarbamateas the TFA salt. LC/MS (10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)),m/z: M+1 obs=437.3; t_(R)=2.18 minutes.

Method B

A solution of2-(4-((S)-3-(aminomethyl)pyrrolidin-1-yl)-7-methylquinazolin-2-yl)phenol(0.12 g, 0.35 mmol) and triethylamine (98 μL, 0.7 mmol) in anhydrous DMF(4.0 mL) was cooled in an ice bath. 2-Methoxyethyl chloroformate (40 mL,0.35 mmol) was added, and the ice bath was removed. The solution wasstirred at room temperature overnight. Purification via silica gelchromatography using 0-10% MeOH in CH₂Cl₂ gave 2-methoxyethyl((S)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-yl)methylcarbamate(0.12 g, 80%). LC/MS: m/z 437.5 (M+H)⁺ at 2.20 min (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)).

2-Methoxyethyl((S)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-yl)methylcarbamatehydrochloride

A 1.0 M HCl solution in Et₂O (0.27 mL, 0.27 mmol) was slowly added to astirring solution of 2-methoxyethyl((S)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-yl)methylcarbamate(0.12 g, 0.27 mmol) in CH₂Cl₂ (5 mL). The reaction was stirred for 30minutes at room temperature, then Et₂O was slowly added to the solutionuntil a precipitate formed. After stirring for 1 h, the solid wasfiltered and washed with Et₂O to obtain 2-methoxyethyl((S)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-yl)methylcarbamatehydrochloride (0.10 g, 77%). LC/MS: m/z 437.1 (M+H)⁺ at 2.19 min(10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)).

Example 367 Propyl((S)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-yl)methylcarbamate

Propyl((S)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-yl)methylcarbamate

Method A

Propyl chloroformate (12 mg, 0.10 mmol) and triethylamine (30 mg, 42 μL,0.30 mmol) were added to2-(4-((S)-3-(aminomethyl)pyrrolidin-1-yl)-7-methylquinazolin-2-yl)phenol(33 mg, 0.10 mmol) in 1 mL anhydrous DMF. The reaction was stirred atroom temperature overnight, filtered, and purified by reverse phase HPLC(10%-99% CH₃CN (0.035% TFA)/H₂O (0:05% TFA)) to give propyl((S)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-yl)methylcarbamateas the TFA salt. LC/MS: m/z 421.1 (M+H)⁺ at 2.43 min (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)).

Method B

A solution of2-(4-((S)-3-(aminomethyl)pyrrolidin-1-yl)-7-methylquinazolin-2-yl)phenol(301 mg, 0.9 mmol) in CH₂Cl₂ (10 ml) was stirred under an N₂ atmosphere.Triethylamine (0.25 mL, 1.8 mmol) was added, and the solution was cooledto −30° C. A 1 M propyl chloroformate solution (0.1 mL in 0.9 mL CH₂Cl₂,0.9 mmol) was added, and the reaction mixture was allowed to warm toroom temperature over a period of 30 minutes. After adding CH₂Cl₂ to thereaction mixture, it was washed 2 times with water, before it was driedover Na₂SO₄, filtered, and concentrated. Purification via silica gelchromatography using 0-20% EtOAc in CH₂Cl₂ gave propyl((S)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-yl)methylcarbamate(236 mg, 62%). LC/MS: m/z 421 (M+H)⁺ at 2.54 min (10%-99% CH₃CN (0.035%TFA)/H₂O (0.05% TFA)). ¹H NMR (400 MHz, DMSO-d6) δ 8.43 (dd, J=8.2, 1.8Hz, 1H), 8.21 (d, J=8.7 Hz, 1H), 7.58 (s, 1H), 7.39-7.31 (m, 3H),6.93-6.89 (m, 2H), 4.09-3.86 (m, 6H), 3.78-3.73 (m, 1H), 3.21-3.09 (m,2H), 2.49 (s, 3H), 2.15-2.09 (m, 1H), 1.83-1.74 (m, 1H), 1.62-1.48 (m,2H), 0.89-0.86 (m, 3H) ppm.

Propyl((S)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-yl)methylcarbamatehydrochloride

A solution of propyl((S)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-yl)methylcarbamate(232 mg, 0.552 mmol) in CH₂Cl₂ (2 mL) was stirred under an N₂atmosphere. A 2.0 M HCl solution in ether (0.276 mL, 0.552 mmol) wasadded dropwise to this solution. After 10 minutes, ether (8 mL) wasadded until a precipitate formed, which was filtered and dried to obtainpropyl((S)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-yl)methylcarbamatehydrochloride (223 mg, 88%). LC/MS: m/z 421 (M+H)⁺ at 2.54 min (10%-99%CH₃CN (0.035% TFA)/H₂O (0.05% TFA)). ¹H NMR (400 MHz, DMSO-d6) δ 8.31(d, J=8.7 Hz, 1H), 8.24 (dd, J=7.9, 1.4 Hz, 1H), 7.82 (s, 1H), 7.54-7.49(m, 2H), 7.41-7.37 (m, 1H), 7.14 (d, J=8.1 Hz, 1H), 7.06-7.02 (m, 1H),4.29-3.78 (m, 7H), 3.24-3.08 (m, 2H), 2.54 (s, 3H), 2.18-2.12 (m, 1H),1.84-1.79 (m, 1H), 1.59-1.50 (m, 2H), 0.87 (t, J=7.4 Hz, 3H) ppm.

Example 368 Isopropyl((S)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-yl)methylcarbamate

Isopropyl((S)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-yl)methylcarbamate

Isopropyl chloroformate (12 mg, 0.10 mmol) and triethylamine (30 mg, 42μL, 0.30 mmol) were added to a solution of2-(4-((S)-3-(aminomethyl)pyrrolidin-1-yl)-7-methylquinazolin-2-yl)phenol(33 mg, 0.10 mmol) in 1 mL anhydrous DMF. The reaction was stirred atroom temperature overnight, filtered, and purified by reverse phase HPLC(10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)) to give isopropyl((S)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-yl)methylcarbamateas the TFA salt. LC/MS: m/z 421.1 (M+H)⁺ at 2.42 min (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)).

Example 369 Neopentyl((S)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-yl)methylcarbamate

Neopentyl((S)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-yl)methylcarbamate

Method A

Neopentyl chloroformate (15 mg, 0.10 mmol) and triethylamine (30 mg, 42μL, 0.30 mmol) were added to a solution of2-(4-((S)-3-(aminomethyl)pyrrolidin-1-yl)-7-methylquinazolin-2-yl)phenol(33 mg, 0.10 mmol) in 1 mL anhydrous DMF. The reaction was stirred atroom temperature overnight, filtered, and purified by reverse phase HPLC(10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)) to give neopentyl((S)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-yl)methylcarbamateas the TFA salt. LC/MS: m/z 449.3 (M+H)⁺ at 2.67 min (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)).

Method B

A mixture of2-(4-((S)-3-(aminomethyl)pyrrolidin-1-yl)-7-methylquinazolin-2-yl)phenol(200 mg, 0.6 mmol), DMF (6.0 mL), and DMF (1 mL) was stirred under an N₂atmosphere. Triethylamine (0.166 mL, 1.2 mmol) was added, and thereaction was cooled in an ice bath. To this was added 1 M neopentylchloroformate solution (89 μL in 600 μL THF, 0.6 mmol). After allowingthe reaction mixture to warm to room temperature over a period of 30minutes, CH₂Cl₂ was added to the reaction mixture, and it was washedonce with water before it was dried over Na₂SO₄, filtered, andconcentrated. Purification via silica gel chromatography using 0-20%EtOAc in CH₂Cl₂/hexanes (1:1) gave neopentyl((S)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-yl)methylcarbamate(222 mg, 94%). LC/MS: m/z 449 (M+H)⁺ at 2.73 min (10%-99% CH₃CN (0.035%TFA)/H₂O (0.05% TFA)). ¹H NMR (400 MHz, acetic acid-d4) δ 8.42 (dd,J=8.1, 1.8 Hz, 1H), 8.20 (d, J=8.7 Hz, 1H), 7.57 (s, 1H), 7.40-7.29 (m,3H), 6.92-6.89 (m, 2H), 4.11-3.92 (m, 3H), 3.78-3.61 (m, 3H), 3.33-3.28(m, 1H), 3.23-3.10 (m, 2H), 2.49 (s, 3H), 2.16-2.08 (m, 1H), 1.83-1.75(m, 1H), 0.89 (s, 9H) ppm.

Neopentyl((S)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-yl)methylcarbamatehydrochloride

A solution of neopentyl((S)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-yl)methylcarbamate(215 mg, 0.48 mmol) in CH₂Cl₂ (2 ml) was stirred under an N₂ atmosphere.A 1.0 M HCl solution in ether (0.48 ml, 0.48 mmol) was added dropwise tothis solution. After 10 minutes, ether (8 ml) was added until aprecipitate formed, which was filtered and dried to obtain neopentyl((S)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-yl)methylcarbamatehydrochloride (214 mg, 92%). LC/MS: m/z 449 (M+H)⁺ at 2.75 min (10%-99%CH₃CN (0.035% TFA)/H₂O (0.05% TFA)).

Example 370 tert-Butyl(S)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-ylcarbamate

tert-Butyl(S)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-ylcarbamate

tert-Butyl (S)-pyrrolidin-3-ylcarbamate (245 mg, 1.31 mmol) wasdissolved in 1.8 mL of anhydrous CH₂Cl₂ and cooled to 0° C.2-(4-Chloro-7-methylquinazolin-2-yl)phenol (300 mg, 1.1 mmol) dissolvedin 1.8 mL of anhydrous CH₂Cl₂ was added dropwise to the mixture followedby triethylamine (134 mg, 184 μL, 1.32 mmol). The reaction was allowedto warm to room temperature and was stirred overnight. Purification viasilica gel chromatography using 10-100% ethyl acetate/hexanes gavetert-butyl(S)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-ylcarbamate.LC/MS: m/z 421.0 (M+H)⁺ at 2.84 min (10%-99% CH₃CN (0.035% TFA)/H₂O(0.05% TFA)).

Example 371 Isopropyl((S)-1-(2-(2-fluoro-6-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-yl)methylcarbamate

2-(4-((S)-3-(Aminomethyl)pyrrolidin-1-yl)-7-methylquinazolin-2-yl)-3-fluorophenol

A mixture of ((S)-pyrrolidin-3-yl)methanamine (0.6 g, 6.0 mmol), Na₂CO₃(2.2 g, 21 mmol) and methyl isobutyl ketone (12 mL, 6.0 mmol) under anN₂ atmosphere was refluxed overnight using a Dean Stark apparatus. Afterallowing the reaction to cool to room temperature,2-(4-chloro-7-methylquinazolin-2-yl)-3-fluorophenol (1.73 g, 5.99 mmol)was added, and the mixture was stirred overnight at room temperatureunder an N₂ atmosphere. The reaction was then quenched with water. Theaqueous layer was extracted twice with CH₂Cl₂. The organic extracts werecombined, dried over Na₂SO₄, filtered, and concentrated to obtain acrude material containing2-(4-((S)-3-((E)-(4-methylpentan-2-ylideneamino)methyl)pyrrolidin-1-yl)-7-methylquinazolin-2-yl)-3-fluorophenolwhich was then hydrolyzed by heating at 50° C. in 80 mL of awater/isopropanol mixture (1:1) for 6 hours. The reaction was cooled toroom temperature, and the aqueous layer was extracted twice with CH₂Cl₂,dried over Na₂SO₄, filtered, and concentrated. Purification via silicagel chromatography using 5-20% MeOH and CH₂Cl₂ afforded2-(4-((S)-3-(aminomethyl)pyrrolidin-1-yl)-7-methylquinazolin-2-yl)-3-fluorophenol(400 mg, 19% after 3 steps). LC/MS: m/z 353.1 (M+H)⁺ at 1.22 min(10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)).

Isopropyl((S)-1-(2-(2-fluoro-6-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-yl)methylcarbamate

Isopropyl chloroformate (10 mg, 0.09 mmol) was added to a solution of2-(4-((S)-3-(aminomethyl)pyrrolidin-1-yl)-7-methylquinazolin-2-yl)-3-fluorophenol(0.03 g, 0.09 mmol) and triethylamine (25 mL, 0.18 mmol) in DMF (0.6 mL)at −78° C. (external temperature). The reaction mixture was warmed toroom temperature, filtered, and purified via reverse phase HPLC (10%-99%CH₃CN (0.035% TFA)/H₂O (0.05% TFA)) to afford isopropyl((S)-1-(2-(2-fluoro-6-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-yl)methylcarbamateas the TFA salt. LC/MS: m/z 439.5 (M+H)⁺ at 2.31 min (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)).

Example 372 Isobutyl((S)-1-(2-(2-fluoro-6-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-yl)methylcarbamate

Isobutyl((S)-1-(2-(2-fluoro-6-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-yl)methylcarbamate

Isobutyl chloroformate (12 mg, 0.09 mmol) was added to a solution of2-(4-((S)-3-(aminomethyl)pyrrolidin-1-yl)-7-methylquinazolin-2-yl)-3-fluorophenol(0.03 g, 0.09 mmol) and triethylamine (25 mL, 0.18 mmol) in DMF (0.6 mL)at −70° C. (external temperature). The reaction mixture was warmed toroom temperature, filtered, and purified via reverse phase HPLC (10%-99%CH₃CN (0.035% TFA)/H₂O (0.05% TFA)) to afford isobutyl((S)-1-(2-(2-fluoro-6-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-yl)methylcarbamateas the TFA salt. LC/MS: m/z 453.5 (M+H)⁺ at 2.46 min (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)).

Example 373 2-Methoxyethyl((S)-1-(2-(2-fluoro-6-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-yl)methylcarbamate

2-Methoxyethyl((S)-1-(2-(2-fluoro-6-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-yl)methylcarbamate

2-Methoxyethyl chloroformate (12 mg, 0.09 mmol) was added to a solutionof2-(4-((S)-3-(aminomethyl)pyrrolidin-1-yl)-7-methylquinazolin-2-yl)-3-fluorophenol(0.03 g, 0.09 mmol) and triethylamine (25 mL, 0.18 mmol) in DMF (0.6 mL)at −78° C. The reaction mixture was warmed to room temperature,filtered, and purified via reverse phase HPLC (10%-99% CH₃CN (0.035%TFA)/H₂O (0.05% TFA)) to afford 2-methoxyethyl((S)-1-(2-(2-fluoro-6-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-yl)methylcarbamateas the TFA salt. LC/MS: m/z 455.5 (M+H)⁺ at 2.11 min (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)).

Example 374 Propyl((S)-1-(6-fluoro-2-(2-hydroxyphenyl)quinazolin-4-yl)pyrrolidin-3-yl)methylcarbamate

Propyl((S)-1-(6-fluoro-2-(2-hydroxyphenyl)quinazolin-4-yl)pyrrolidin-3-yl)methylcarbamate

To a solution of2-(4-((S)-3-(aminomethyl)pyrrolidin-1-yl)-6-fluoroquinazolin-2-yl)phenol(0.03 g, 0.09 mmol) in DMF (1.0 mL) at −60° C. (external temperature)was added triethylamine (25 mL, 0.18 mmol), followed by the addition ofpropyl chloroformate (11 mg, 0.09 mmol). The reaction was warmed to roomtemperature, filtered, and purified via reverse phase HPLC (10%-99%CH₃CN (0.035% TFA)/H₂O (0.05% TFA)) to afford propyl((S)-1-(6-fluoro-2-(2-hydroxyphenyl)quinazolin-4-yl)pyrrolidin-3-yl)methylcarbamateas the TFA salt. LC/MS: m/z 425.3 (M+H)⁺ at 2.31 min (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)).

Example 375 Neopentyl((S)-1-(6-fluoro-2-(2-hydroxyphenyl)quinazolin-4-yl)pyrrolidin-3-yl)methylcarbamate

Neopentyl((S)-1-(6-fluoro-2-(2-hydroxyphenyl)quinazolin-4-yl)pyrrolidin-3-yl)methylcarbamate

To a solution of2-(4-((S)-3-(aminomethyl)pyrrolidin-1-yl)-6-fluoroquinazolin-2-yl)phenol(0.03 g, 0.09 mmol) in DMF (1.0 mL) at −60° C. (external temperature)was added triethylamine (25 mL, 0.18 mmol), followed by the addition ofneopentyl chloroformate (13 mg, 0.09 mmol). The reaction was warmed toroom temperature, filtered, and purified via reverse phase HPLC (10%-99%CH₃CN (0.035% TFA)/H₂O (0.05% TFA)) to afford neopentyl((S)-1-(6-fluoro-2-(2-hydroxyphenyl)quinazolin-4-yl)pyrrolidin-3-yl)methylcarbamateas the TFA salt. LC/MS: m/z 453.5 (M+H)⁺ at 2.88 min (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)).

Example 376 Isobutyl((S)-1-(6-fluoro-2-(2-hydroxyphenyl)quinazolin-4-yl)pyrrolidin-3-yl)methylcarbamate

Isobutyl((S)-1-(6-fluoro-2-(2-hydroxyphenyl)quinazolin-4-yl)pyrrolidin-3-yl)methylcarbamate

To a solution of2-(4-((S)-3-(aminomethyl)pyrrolidin-1-yl)-6-fluoroquinazolin-2-yl)phenol(0.03 g, 0.09 mmol) in DMF (1.0 mL) at −60° C. (external temperature)was added triethylamine (25 mL, 0.18 mmol), followed by the addition ofisobutyl chloroformate (12 mg, 0.09 mmol). The reaction was warmed toroom temperature, and filtered and purification via reverse phase HPLC(10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)) gave isobutyl((S)-1-(6-fluoro-2-(2-hydroxyphenyl)quinazolin-4-yl)pyrrolidin-3-yl)methylcarbamateas the TFA salt. LC/MS: m/z 439.5 (M+H)⁺ at 2.76 min (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)).

Example 377 2-Methoxyethyl((S)-1-(6-fluoro-2-(2-hydroxyphenyl)quinazolin-4-yl)pyrrolidin-3-yl)methylcarbamate

2-Methoxyethyl((S)-1-(6-fluoro-2-(2-hydroxyphenyl)quinazolin-4-yl)pyrrolidin-3-yl)methylcarbamate

To a solution of2-(4-((S)-3-(aminomethyl)pyrrolidin-1-yl)-6-fluoroquinazolin-2-yl)phenol(0.03 g, 0.09 mmol) in DMF (1.0 mL) at −60° C. (external temperature)was added triethylamine (25 mL, 0.18 mmol), followed by the addition of2-methoxyethyl chloroformate (12 mg, 0.09 mmol). The reaction was warmedto room temperature, and filtered and purification via reverse phaseHPLC (10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)) gave 2-methoxyethyl((S)-1-(6-fluoro-2-(2-hydroxyphenyl)quinazolin-4-yl)pyrrolidin-3-yl)methylcarbamateas the TFA salt. LC/MS: m/z 441.5 (M+H)⁺ at 2.30 min (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)).

Example 4011-(2-(2-Hydroxyphenyl)-7-methylquinazolin-4-yl)-N-((pyridin-4-yl)methyl)azetidine-3-carboxamide

1-(2-(2-Hydroxyphenyl)-7-methylquinazolin-4-yl)azetidine-3-carboxylicacid

To a solution of 2-(4-chloro-7-methylquinazolin-2-yl)phenol (2.84 g,10.5 mmol) and azetidine-3-carboxylic acid (1.06 g, 10.5 mmol) in DMF(100 mL) was added triethylamine (3.18 g, 4.39 mL, 31.5 mmol). Thereaction was stirred at room temperature overnight then diluted with H₂O(400 mL). The pH of the solution was adjusted to 3-4 by addition of anaqueous 1 M HCl solution. The white precipitate then obtained wasfiltered, washed with H₂O, and purified by silica gel chromatographyusing 0-15% MeOH—CH₂Cl₂ giving1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)azetidine-3-carboxylicacid. LC/MS: m/z 336.3 (M+H)⁺ at 1.97 min (10%-99% CH₃CN (0.035%TFA)/H₂O (0.05% TFA)).

1-(2-(2-Hydroxyphenyl)-7-methylquinazolin-4-yl)-N-((pyridin-4-yl)methyl)azetidine-3-carboxamide

To a solution of1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)azetidine-3-carboxylicacid (34 mg, 0.1 mmol) and HATU (57 mg, 0.15 mmol) in DMF (1 mL) wasadded (pyridin-4-yl)methanamine (32 mg, 30 μL, 0.30 mmol). The reactionwas stirred at room temperature overnight, filtered, and purified byreverse phase HPLC (10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)) giving1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)-N-((pyridin-4-yl)methyl)azetidine-3-carboxamideas the TFA salt. LC/MS: m/z 426.3 (M+H)⁺ at 1.72 min (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)).

Example 4021-(2-(2-Hydroxyphenyl)-7-methylquinazolin-4-yl)-N-((pyridin-3-yl)methyl)azetidine-3-carboxamide

1-(2-(2-Hydroxyphenyl)-7-methylquinazolin-4-yl)azetidine-3-carboxylicacid

To a solution of 2-(4-chloro-7-methylquinazolin-2-yl)phenol (2.84 g,10.5 mmol) and azetidine-3-carboxylic acid (1.06 g, 10.5 mmol) in DMF(100 mL) was added triethylamine (3.18 g, 4.39 mL, 31.5 mmol). Thereaction was stirred at room temperature overnight then diluted with H₂O(400 mL). The pH of the solution was adjusted to 3-4 by addition of anaqueous 1 M HCl solution. The white precipitate then obtained wasfiltered, washed with H₂O, and purified by silica gel chromatographyusing 0-15% MeOH—CH₂Cl₂ giving1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)azetidine-3-carboxylicacid. LC/MS: m/z 336.3 (M+H)⁺ at 1.97 min (10%-99% CH₃CN (0.035%TFA)/H₂O (0.05% TFA)).

1-(2-(2-Hydroxyphenyl)-7-methylquinazolin-4-yl)-N-((pyridin-3-yl)methyl)azetidine-3-carboxamide

To a solution of1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)azetidine-3-carboxylicacid (34 mg, 0.1 mmol) and HATU (57 mg, 0.15 mmol) in DMF (1 mL) wasadded (pyridin-3-yl)methanamine (32 mg, 30 μL, 0.30 mmol). The reactionwas stirred at room temperature overnight, filtered, and purified byreverse phase HPLC (10%-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA)) to give1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)-N-((pyridin-3-yl)methyl)azetidine-3-carboxamideas the TFA salt. LC/MS: m/z 426.3 (M+H)⁺ at 1.72 min (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)).

Example 403N-(3-(Trifluoromethoxy)benzyl)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)azetidine-3-carboxamide

N-(3-(Trifluoromethoxy)benzyl)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)azetidine-3-carboxamide

To a solution of1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)azetidine-3-carboxylicacid (34 mg, 0.10 mmol) and HATU (57 mg, 0.15 mmol) in DMF (1 mL) wasadded (3-(trifluoromethoxy)phenyl)methanamine (57 μL, 0.30 mmol). Thereaction was stirred at room temperature overnight, filtered, andpurified by reverse phase HPLC (10%-99% CH₃CN (0.035% TFA)/H₂O (0.05%TFA)) to giveN-(3-(trifluoromethoxy)benzyl)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)azetidine-3-carboxamideas the TFA salt. LC/MS: m/z 509.3 (M+H)⁺ at 2.73 min (10%-99% CH₃CN(0.035% TFA)/H₂O (0.05% TFA)).

Table 3 below recites analytical data for exemplary compounds of thepresent invention.

TABLE 3 LC-MS LC-RT Cmpd No. M + 1 min 101 449.3 2.79 102 421 2.48 103499.3 2.97 104 464.5 2.03 105 447.1 2.32 106 465.5 2.47 107 442.5 1.97108 407.5 2.21 109 393.1 2.04 110 461.1 2.56 111 453.5 3.21 112 461.32.49 113 421.1 2.76 114 474.3 1.19 115 421.3 2.51 116 442.5 1.96 117439.5 2.79 118 393.3 2.22 119 465.2 2.5 120 435.3 2.65 121 393.3 2.21122 435.3 2.56 123 465.3 2.5 124 407.5 2.29 125 453.4 2.79 126 471.22.93 127 445.5 3.32 128 451.5 2.62 129 407.5 2.31 130 469.3 2.87 131469.4 2.88 132 456.5 2.04 133 454.3 1.94 134 421.1 2.46 135 467.1 2.59136 453.3 3.02 137 407.3 2.28 138 453.3 2.43 139 439.5 2.95 140 485.52.94 141 459.3 2.13 142 446.3 3.17 143 439.5 2.99 144 435.3 2.9 145437.3 2.04 146 455.5 2.45 147 453.3 2.4 148 439.5 2.8 149 465.5 2.23 150449.3 2.22 151 435.5 2.13 152 456.5 2.02 153 453.4 2.73 154 436.3 1.94155 477.5 2.96 156 474.3 1.19 157 485.4 3.02 158 403.5 2.34 159 421.32.6 160 467.3 3.13 162 467.3 2.33 163 453.3 2.25 164 451.3 2.18 165421.3 2.4 166 434.53 2.61 167 491.3 2.46 168 435.3 2.91 169 577.4 2.5170 473.1 2.63 171 517.5 3.49 172 465 2.77 173 393.1 2.03 174 407.5 2.41175 460.5 2.33 176 435.5 2.62 177 447.1 2.53 178 447.3 2.5 179 427.22.59 180 435.2 2.88 181 435.3 2.69 182 435.3 2.5 183 435.3 2.5 184 449.32.5 185 449.3 2.56 186 419.3 2.9 187 419.3 2.38 188 467.5 2.58 189 433.52.59 190 477.2 2.83 191 435.5 2.81 192 393.3 2.7 193 435.5 2.54 194553.1 2.42 195 421.3 3.43 196 405.5 2.68 197 435.5 3.2 201 454.5 1.87203 449.3 2.34 204 449.3 2.33 205 433.3 2.33 206 433.5 2.34 207 449.52.34 208 449.5 2.33 209 447.5 2.27 210 463.5 2.34 211 463.5 2.34 212 4172.3 213 453.5 1.98 214 463.5 2.32 215 463.5 2.36 216 463.5 2.35 217463.5 2.35 218 447.5 2.02 219 477.4 2.84 220 447.5 2.19 221 461.5 2.22222 531.3 3.08 223 468.3 1.86 224 437.1 2.54 225 468.6 2.19 226 417.52.3 227 470.5 1.98 228 470.5 1.98 229 513.3 2.82 230 447.3 2.21 231481.1 2.17 232 463.3 2.58 233 421.2 2.17 234 449.2 2.42 235 407.5 2.04236 407.3 2.08 237 407.5 2.09 238 435.3 2.4 239 461.1 2.4 240 435.5 2.29241 421.1 2.24 242 421.3 2.18 243 421.3 2.18 244 421.3 2.18 245 449.32.45 246 475.1 2.46 247 435.3 2.31 248 435.3 2.24 249 481.3 2.42 250449.5 2.77 251 421 2.48 252 449.3 2.8 253 449.5 2.78 254 421.1 2.5 255435.5 2.61 256 435.5 2.61 257 451.1 2.34 258 441.5 2.6 259 435.2 3.03260 467.1 2.56 261 469.1 2.2 262 439.3 2.31 264 435.1 2.6 265 449.3 2.72266 449.2 2.55 267 449.3 2.58 268 449.1 2.54 269 449.5 2.57 270 435.22.88 271 447.2 2.46 272 449.2 2.57 273 449.2 2.57 274 463.4 2.42 275463.4 2.43 276 433.2 2.33 277 433.2 2.32 278 449.2 2.85 279 435.4 2.61280 491 2.73 281 505.2 2.71 282 435.5 2.8 283 433.2 2.33 301 435 2.41302 419 2.35 303 419 2.34 304 435 2.39 305 449.3 2.18 306 449.3 2.16 307449.3 2.18 308 433.5 2.11 309 455.2 2.81 310 433.5 2.13 311 403.7 2.17312 389.2 2.38 313 441 2.78 314 463.4 2.66 315 432.5 2.24 316 433.5 2.05317 447.3 2.07 318 454.3 1.79 319 456.5 1.85 320 456.5 1.84 321 499.32.57 322 454.4 2.08 323 445.4 2.85 324 460.4 2.1 325 509.5 2.71 326455.3 2.43 327 450.3 2.39 328 426.3 1.91 329 393.3 2.23 330 465.4 2.88331 477.3 2.81 332 511.5 3.07 333 443.5 2.83 334 511.5 3.1 335 439.52.25 336 493.5 3.03 337 439.5 2.25 338 451.5 2.15 339 467.3 2.5 340445.4 2.95 341 443.4 2.73 342 468.4 2.39 343 493.4 2.76 344 443.3 2.69345 453.3 2.05 346 407.5 2.2 347 430.5 1.95 348 430.5 2.43 349 430.51.98 350 444.5 1.85 351 444.5 2.24 352 444.5 1.89 353 426.1 1.93 354426.1 2.33 355 453.3 2.29 356 453.3 2.29 357 407.3 2.26 358 477.3 2.8359 491.3 2.24 360 473.1 2.32 361 449.3 2.4 362 469.1 2.58 363 469.12.58 364 407.7 2.3 365 435.3 2.57 366 437.3 2.18 367 421.1 2.44 368421.1 2.43 369 449.3 2.67 370 421 2.84 371 439.5 2.31 372 453.5 2.46 373455.5 2.11 374 425.3 2.31 375 453.5 2.88 376 439.5 2.76 377 441.5 2.3378 491.2 2.58 379 441.2 2.72 380 419.5 2.5 401 426.3 1.72 402 426.31.72 403 509.3 2.73 404 393.2 1.95 405 421.2 2.29 406 421.2 2.2 407435.4 2.23 408 435.4 2.16 409 421.2 2.15 410 421.1 2.4 411 435.2 2.24412 405.2 2.09 413 435.4 2.16 414 435.2 2.17 415 449.2 2.25 416 435.32.25 417 419.4 2.06 418 421.2 2.57 419 423.2 2.15 420 407.2 2.42

Methods:

(A) Micromass MUX LCT 4 channel LC/MS, Waters 60F pump, Gilson 215 4probe autosampler, Gilson 849 injection module, 1.5 mL/min/column flowrate, 10-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA) gradient, PhenomenexLuna 5u C18 columns (50×4.60 mm), Waters MUX UV-2488 UV detector, Cedex75 ELSD detectors.

(B) PESciex API-150-EX LC/MS, Shimadzu LC-8A pumps, Gilson 215autosampler, Gilson 819 injection module, 3.0 m/min flow rate, 10-99%CH₃CN (0.035% TFA)/H₂O (0.05% TFA) gradient, Phenomenex Luna 5u C18column (50×4.60 mm), Shimadzu SPD-10A UV/Vis detector, Cedex 75 ELSDdetector.

(C) PESciex API-150-EX LC/MS, Shimadzu LC-8A pumps, Gilson 215autosampler, Gilson 819 injection module, 3.0 mL/min flow rate, 40-99%CH₃CN (0.035% TFA)/H₂O (0.05% TFA) gradient, Phenomenex Luna 5u C18column (50×4.60 mm), Shimadzu SPD-10A UV/Vis detector, Cedex 75 ELSDdetector.

Assays for Detecting and Measuring NaV Inhibition Properties ofCompounds

A) Optical Methods for Assaying NaV Inhibition Properties of Compounds:

Compounds of the invention are useful as antagonists of voltage-gatedsodium ion channels. Antagonist properties of test compounds wereassessed as follows. Cells expressing the NaV of interest were placedinto microtiter plates. After an incubation period, the cells werestained with fluorescent dyes sensitive to the transmembrane potential.The test compounds were added to the microtiter plate. The cells werestimulated with either a chemical or electrical means to evoke a NaVdependent membrane potential change from unblocked channels, which wasdetected and measured with trans-membrane potential-sensitive dyes.Antagonists were detected as a decreased membrane potential response tothe stimulus. The optical membrane potential assay utilizedvoltage-sensitive FRET sensors described by Gonzalez and Tsien (See,Gonzalez, J. E. and R. Y. Tsien (1995) “Voltage sensing by fluorescenceresonance energy transfer in single cells” Biophys J 69(4): 1272-80, andGonzalez, J. E. and R. Y. Tsien (1997) “Improved indicators of cellmembrane potential that use fluorescence resonance energy transfer” ChemBiol 4(4): 269-77) in combination with instrumentation for measuringfluorescence changes such as the Voltage/Ion Probe Reader (VIPR®) (See,Gonzalez, J. E., K. Oades, et al. (1999) “Cell-based assays andinstrumentation for screening ion-channel targets” Drug Discov Today4(9): 431-439).

B) VIPR® Optical Membrane Potential Assay Method with ChemicalStimulation

Cell Handling and Dye Loading

24 hours before the assay on VIPR, CHO cells endogenously expressing aNaV1.2 type voltage-gated NaV are seeded in 96-well poly-lysine coatedplates at 60,000 cells per well. Other subtypes are performed in ananalogous mode in a cell line expressing the NaV of interest.

-   1) On the day of the assay, medium is aspirated and cells are washed    twice with 225 μL of Bath Solution #2 (BS#2).-   2) A 15 uM CC2-DMPE solution is prepared by mixing 5 mM coumarin    stock solution with 10% Pluronic 127 1:1 and then dissolving the mix    in the appropriate volume of BS#2.-   3) After bath solution is removed from the 96-well plates, the cells    are loaded with 80 μL of the CC2-DMPE solution. Plates are incubated    in the dark for 30 minutes at room temperature.-   4) While the cells are being stained with coumarin, a 15 μL oxonol    solution in BS#2 is prepared. In addition to DiSBAC₂(3), this    solution should contain 0.75 mM ABSCl and 30 μL veratridine    (prepared from 10 mM EtOH stock, Sigma #V-5754).-   5) After 30 minutes, CC2-DMPE is removed and the cells are washed    twice with 225 μL of BS#2. As before, the residual volume should be    40 μL.-   6) Upon removing the bath, the cells are loaded with 80 μL of the    DiSBAC₂(3) solution, after which test compound, dissolved in DMSO,    is added to achieve the desired test concentration to each well from    the drug addition plate and mixed thoroughly. The volume in the well    should be roughly 121 μL. The cells are then incubated for 20-30    minutes.-   7) Once the incubation is complete, the cells are ready to be    assayed on VIPR® with a sodium add back protocol. 120 μL of Bath    solution #1 is added to stimulate the NaV dependent depolarization.    200 μL tetracaine was used as an antagonist positive control for    block of the NaV channel.

Analysis of VIPR® Data:

Data are analyzed and reported as normalized ratios ofbackground-subtracted emission intensities measured in the 460 nm and580 nm channels. Background intensities are then subtracted from eachassay channel. Background intensities are obtained by measuring theemission intensities during the same time periods from identicallytreated assay wells in which there are no cells. The response as afunction of time is then reported as the ratios obtained using thefollowing formula:

${R(t)} = \frac{\left( {{intensity}_{460\;{nm}} - {background}_{460\;{nm}}} \right)}{\left( {{intensity}_{580\;{nm}} - {background}_{580\;{nm}}} \right)}$

The data is further reduced by calculating the initial (R_(i)) and final(R_(f)) ratios. These are the average ratio values during part or all ofthe pre-stimulation period, and during sample points during thestimulation period. The response to the stimulus R=R_(f)/R_(i) is thencalculated. For the Na⁺ addback analysis time windows, baseline is 2-7sec and final response is sampled at 15-24 sec.

Control responses are obtained by performing assays in the presence of acompound with the desired properties (positive control), such astetracaine, and in the absence of pharmacological agents (negativecontrol). Responses to the negative (N) and positive (P) controls arecalculated as above. The compound antagonist activity A is defined as:

$A = {\frac{R - P}{N - P}*100.}$where R is the ratio response of the test compoundSolutions [mM]

-   Bath Solution #1: NaCl 160, KCl 4.5, CaCl₂ 2, MgCl₂ 1, HEPES 10, pH    7.4 with NaOH-   Bath Solution #2 TMA-Cl 160, CaCl₂ 0.1, MgCl₂ 1, HEPES 10, pH 7.4    with KOH (final K Concentration ˜5 mM)-   CC2-DMPE: prepared as a 5 mM stock solution in DMSO and stored at    −20° C.-   DiSBAC₂(3): prepared as a 12 mM stock in DMSO and stored at −20° C.-   ABSCl : prepared as a 200 mM stock in distilled H₂O and stored at    room temperature

Cell Culture

CHO cells are grown in DMEM (Dulbecco's Modified Eagle Medium; GibcoBRL#10569-010) supplemented with 10% FBS (Fetal Bovine Serum, qualified;GibcoBRL #16140-071) and 1% Pen-Strep (Penicillin-Streptomycin; GibcoBRL#15140-122). Cells are grown in vented cap flasks, in 90% humidity and10% CO₂, to 100% confluence. They are usually split by trypsinization1:10 or 1:20, depending on scheduling needs, and grown for 2-3 daysbefore the next split.

C) VIPR® Optical Membrane Potential Assay Method with ElectricalStimulation

The following is an example of how NaV1.3 inhibition activity ismeasured using the optical membrane potential method#2. Other subtypesare performed in an analogous mode in a cell line expressing the NaV ofinterest.

HEK293 cells stably expressing NaV1.3 are plated into 96-well microtiterplates. After an appropriate incubation period, the cells are stainedwith the voltage sensitive dyes CC2-DMPE/DiSBAC2(3) as follows.

Reagents:

-   100 mg/mL Pluronic F-127 (Sigma #P2443), in dry DMSO-   10 mM DiSBAC₂(3) (Aurora #00-100-010) in dry DMSO-   10 mM CC2-DMPE (Aurora #00-100-008) in dry DMSO-   200 mM ABSCl in H₂O    Hank's Balanced Salt Solution (Hyclone #SH30268.02) supplemented    with 10 mM HEPES (Gibco #15630-080)

Loading Protocol:

2×CC2-DMPE=20 μM CC2-DMPE: 10 mM CC2-DMPE is vortexed with an equivalentvolume of 10% pluronic, followed by vortexing in required amount of HBSScontaining 10 mM HEPES. Each cell plate will require 5 mL of 2×CC2-DMPE.50 μL of 2×CC2-DMPE is to wells containing washed cells, resulting in a10 μM final staining concentration. The cells are stained for 30 minutesin the dark at RT.

2×DISBAC₂(3) with ABSCl=6 μM DISBAC₂(3) and 1 mM ABSCl: The requiredamount of 10 mM DISBAC₂(3) is added to a 50 ml conical tube and mixedwith 1 μL 10% pluronic for each mL of solution to be made and vortexedtogether. Then HBSS/HEPES is added to make up 2× solution. Finally, theABSCl is added.

The 2×DiSBAC₂(3) solution can be used to solvate compound plates. Notethat compound plates are made at 2× drug concentration. Wash stainedplate again, leaving residual volume of 50 μL. Add 50 uL/well of the2×DiSBAC₂(3) w/ABSCl. Stain for 30 minutes in the dark at RT.

The electrical stimulation instrument and methods of use are describedin ION Channel Assay Methods PCT/US01/21652, herein incorporated byreference. The instrument comprises a microtiter plate handler, anoptical system for exciting the coumarin dye while simultaneouslyrecording the coumarin and oxonol emissions, a waveform generator, acurrent- or voltage-controlled amplifier, and a device for insertingelectrodes in well. Under integrated computer control, this instrumentpasses user-programmed electrical stimulus protocols to cells within thewells of the microtiter plate.

Reagents

Assay buffer #1

140 mM NaCl, 4.5 mM KCl, 2 mM CaCl₂, 1 mM MgCl₂, 10 mM HEPES, 10 mMglucose, pH 7.40, 330 mOsm

-   Pluronic stock (1000×): 100 mg/mL pluronic 127 in dry DMSO-   Oxonol stock (3333×): 10 mM DiSBAC₂(3) in dry DMSO-   Coumarin stock (1000×): 10 mM CC2-DMPE in dry DMSO-   ABSCl stock (400×): 200 mM ABSCl in water

Assay Protocol

-   -   1. Insert or use electrodes into each well to be assayed.    -   2. Use the current-controlled amplifier to deliver stimulation        wave pulses for 3 s. Two seconds of pre-stimulus recording are        performed to obtain the un-stimulated intensities. Five seconds        of post-stimulation recording are performed to examine the        relaxation to the resting state.

Data Analysis

Data are analyzed and reported as normalized ratios ofbackground-subtracted emission intensities measured in the 460 nm and580 nm channels. Background intensities are then subtracted from eachassay channel. Background intensities are obtained by measuring theemission intensities during the same time periods from identicallytreated assay wells in which there are no cells. The response as afunction of time is then reported as the ratios obtained using thefollowing formula:

${R(t)} = \frac{\left( {{intensity}_{460\;{nm}} - {background}_{460\;{nm}}} \right)}{\left( {{intensity}_{580\;{nm}} - {background}_{580\;{nm}}} \right)}$

The data is further reduced by calculating the initial (R_(i)) and final(R_(f)) ratios. These are the average ratio values during part or all ofthe pre-stimulation period, and during sample points during thestimulation period. The response to the stimulus R=R_(f)/R_(i) is thencalculated.

Control responses are obtained by performing assays in the presence of acompound with the desired properties (positive control), such astetracaine, and in the absence of pharmacological agents (negativecontrol). Responses to the negative (N) and positive (P) controls arecalculated as above. The compound antagonist activity A is defined as:

$A = {\frac{R - P}{N - P}*100.}$where R is the ratio response of the test compound.

Electrophysiology Assays for NaV Activity and Inhibition of TestCompounds

Patch clamp electrophysiology was used to assess the efficacy andselectivity of sodium channel blockers in dorsal root ganglion neurons.Rat neurons were isolated from the dorsal root ganglions and maintainedin culture for 2 to 10 days in the presence of NGF (50 ng/ml) (culturemedia consisted of NeurobasalA supplemented with B27, glutamine andantibiotics). Small diameter neurons (nociceptors, 8-12 μm in diameter)have been visually identified and probed with fine tip glass electrodesconnected to an amplifier (Axon Instruments). The “voltage clamp” modehas been used to assess the compound's IC50 holding the cells at −60 mV.In addition, the “current clamp” mode has been employed to test theefficacy of the compounds in blocking action potential generation inresponse to current injections. The results of these experiments havecontributed to the definition of the efficacy profile of the compounds.

Voltage-Clamp Assay in DRG Neurons

TTX-resistant sodium currents were recorded from DRG somata using thewhole-cell variation of the patch clamp technique. Recordings were madeat room temperature (˜22° C.) with thick walled borosilicate glasselectrodes (WPI; resistance 3-4 MΩ) using an Axopatch 200B amplifier(Axon Instruments). After establishing the whole-cell configuration,approximately 15 minutes were allowed for the pipette solution toequilibrate within the cell before beginning recording. Currents werelowpass filtered between 2-5 kHz and digitally sampled at 10 kHz. Seriesresistance was compensated 60-70% and was monitored continuouslythroughout the experiment. The liquid junction potential (−7 mV) betweenthe intracellular pipette solution and the external recording solutionwas not accounted for in the data analysis. Test solutions were appliedto the cells with a gravity driven fast perfusion system (SF-77; WarnerInstruments).

Dose-response relationships were determined in voltage clamp mode byrepeatedly depolarizing the cell from the experiment specific holdingpotential to a test potential of +10 mV once every 60 seconds. Blockingeffects were allowed to plateau before proceeding to the next testconcentration.

Solutions

Intracellular solution (in mM): Cs—F (130), NaCl (10), MgCl₂ (1), EGTA(1.5), CaCl₂ (0.1), HEPES (10), glucose (2), pH=7.42, 290 mOsm.

Extracellular solution (in mM): NaCl (138), CaCl₂ (1.26), KCl (5.33),KH₂PO₄ (0.44), MgCl₂ (0.5), MgSO₄ (0.41), NaHCO₃ (4), Na₂HPO₄ (0.3),glucose (5.6), HEPES (10), CdCl2 (0.4), NiCl2 (0.1), TTX (0.25×10⁻³).

Current-Clamp Assay for NaV Channel Inhibition Activity of Compounds

Cells were current-clamped in whole-cell configuration with a Multiplamp700A amplifier (Axon Inst). Borosilicate pipettes (4-5 MOhm) were filledwith (in mM):150 K-gluconate, 10 NaCl, 0.1 EGTA, 10 Hepes, 2 MgCl₂,(buffered to pH 7.34 with KOH). Cells were bathed in (in mM): 140 NaCl,3 KCl, 1 MgCl, 1 CaCl, and 10 Hepes). Pipette potential was zeroedbefore seal formation; liquid junction potentials were not correctedduring acquisition. Recordings were made at room temperature.

Following these procedures, representative compounds of the presentinvention were found to possess desired voltage gated sodium channelactivity and selectivity.

Assays for Detecting and Measuring L-Type CaV 1.2 Inhibition Propertiesof Compounds

A) Optical methods for assaying CaV inhibition properties of compounds:

Compounds of the invention are useful as antagonists of voltage-gatedcalcium ion channels. Antagonist properties of test compounds wereassessed as follows. Cells expressing the CaV of interest were placedinto microtiter plates. After an incubation period, the cells werestained with fluorescent dyes sensitive to the transmembrane potential.The test compounds were added to the microtiter plate. The cells werestimulated with electrical means to evoke a CaV dependent membranepotential change from unblocked channels, which was detected andmeasured with trans-membrane potential-sensitive dyes. Antagonists weredetected as a decreased membrane potential response to the stimulus. Theoptical membrane potential assay utilized voltage-sensitive FRET sensorsdescribed by Gonzalez and Tsien (See, Gonzalez, J. E. and R. Y. Tsien(1995) “Voltage sensing by fluorescence resonance energy transfer insingle cells” Biophys J 69(4): 1272-80, and Gonzalez, J. E. and R. Y.Tsien (1997) “Improved indicators of cell membrane potential that usefluorescence resonance energy transfer” Chem Biol 4(4): 269-77) incombination with instrumentation for measuring fluorescence changes suchas the Voltage/Ion Probe Reader (VIPR®) (See, Gonzalez, J. E., K. Oades,et al. (1999) “Cell-based assays and instrumentation for screeningion-channel targets” Drug Discov Today 4(9): 431-439).

VIPR® optical membrane potential assay method with electricalstimulation Positive Control (100% Block)

The positive control for this assay was 125 uM mibefradil, achieved byadding 25 uL of 250 uM solution to the assay plates containing 25 uL ofassay buffer. Each assay plate included positive control wells.

Negative Control (No Block)

The negative (baseline) control for this assay was DMSO. This wasachieved by adding 25 uL of 1% DMSO (in assay buffer) to the assayplates containing 25 uL of assay buffer. Each assay plate includednegative control wells.

Background Subtraction

Fluorescence background from plastic in assay plates (or from the assaybuffer) was assessed by running a cell-free plate through the EVIPRunder the same optical configuration. The average background values foreach row and each wavelength were subtracted in MOD3 prior to ratiochange and activity calculations.

Reagents

Assay Buffers:

Bath Y (Prepared by Vertex Lab Support)

-   -   140 mM TMA-Cl    -   4.5 mM KCl    -   1 mM MgCl₂    -   10 mM HEPES, pH7.4    -   10 mM glucose    -   Osmolarity=295mOsm (280-310 acceptable range)

500 mM BaCl₂ (Sigma #B0750), in H₂O

100 mg/mL Pluronic F-127 (Sigma #P2443), in dry DMSO

10 mM DiSBAC₂(3) (Aurora #00-100-010) in dry DMSO

10 mM CC2-DMPE (Aurora #00-100-008) in dry DMSO

200 mM Acid Yellow 17 (Aurora #VABSC) in H₂O

Assay Volume

50 uL

DMSO Conc in Assay

0.5% (1 uL of 75% DMSO/25% water, dilution factor of 160)

Incubation Time of Compounds

20-25 minutes

Instrumentation

This screen was conducted on the Allegro™ system. The system isdiagrammed below: The Allegro™ is equipped with a compound plate storageunit (stacker). The stacker holds a set of trays (each tray holds 12compound plates). The libraries were received from Compound Management,as pre-spotted (1 uL/well of compound and controls) intermediate platesin 384-well format, as a 1.6 mM stock solution in 75% DMSO/25%de-ionized H₂O. The plates are diluted in 80 uL oxonol dye solution tocreate a 2× stock. Three EVIPR readers are integrated to the Allegrosystem by a Mitsubishi robotic arm. Only one EVIPR was used per run.

Instrumentation Settings

Optical:

-   -   Read Frequency: 10 Hz    -   Excitation Wavelength: 400 nm    -   Emission Wavelengths: 460 nm and 560 nm    -   Electrical Stimulation:    -   Pulse Width: 11.1 ms        -   Stimulation Current: 0.8 amps        -   Stimulation Frequency: 90 Hz    -   Pre-stimulation time: 2 s    -   Stimulation time: 3 s    -   Post-stimulation time: 1 s    -   Waveform: Biphasic Square Wave        Plate Washer Settings:    -   Settings for ELx405 washer will leave a residual volume of 25        uL.

Plate Type: 384

# of cycles: 3

Soak/shake: No

Dispense: dispense volume 100 dispense flow rate 1 dispense height 80horizontal disp pos −20 horiz y disp pos −5 Aspirate: aspirate height 48horizontal aspr pos −18 horiz y asp pos −5 aspiration rate 0 aspirationdelay 0 final asp delay 500Assay Procedure

Procedure run on HTS Allegro™:

-   -   1. Carousel: Assay plates (Cell plates) loaded into carousel        module #1 (CO₂=5%, ambient temperature and Rh)    -   2. Barrier: Assay plates retrieved from carousel and passed        through environmental barrier (The remaining steps are conducted        at room temperature and ambient CO₂)    -   3. Washer: Assay plates washed with Bath Y on Biotek ELx405.    -   4. MultiReagent Dispenser (MRD): 25 uL of CC2-DMPE (and equal        volume Pluronic) in Bath Y added to each well to make 10 uM.    -   5. Barrier: Assay plates passed through barrier.    -   6. Carousel: 30-minute incubation at room temperature.    -   7. Barrier: Assay plates passed through barrier.    -   8. Washer: Assay plates washed with Bath Y on Biotek ELx405    -   9. High Density Transfer Station:        -   a. 80 uL oxonol dye loading solution (4 uM DISBAC2(3), 1 mM            VABSC and 30 mM BaCl₂ in BathY) added to compound plates            (pre-spotted with 1 uL compound) using a Multiprop (offline)        -   b. Plates mixed (3 times 20 uL) on CyBiWell (offline).            Plates loaded onto compound tray.        -   c. Compound tray retrieved from compound tray stacker and            compound plate barcodes read.        -   d. Assay plate barcode read and moved to SciClone deck        -   e. 25 uL compound plus oxonol aspirated from compound plate            on SciClone deck and transferred to assay plate.            -   i. Final assay volume=50 uL            -   ii. Final compound concentration=10 uM        -   f. SciClone tips washed in DMSO and 5% ethanol in water to            remove external carry-over.    -   10. Carousel: Assay plates incubated for 20 minutes at RT    -   11. Barrier: Assay plates passed through final barrier    -   12. Mitsubishi Robotic Arm: Retrieves assay plate from barrier        output, delivers cell plates to EVIPR 384-1, and sends command        to initiate EVIPR run.        Assay Window

Assay Window Criteria:

-   -   Passing plates≦0.5, rejected plates>0.5

${{Assay}\mspace{14mu}{Window}} = {\frac{3\left( {{SD}_{FullBlock} + {SD}_{Baseline}} \right)}{\left( {{AVE}_{Baseline} - {AVE}_{FullBlock}} \right)} = {1 - Z^{\prime}}}$Data Reduction

The EVIPR files were reduced to decrease the amount of data pumped intothe database. Two “windows” of interest were filtered out of each EVIPRfile. Each window is a slice of the response measured in each well. Thefirst window is measured before stimulation. The second window samplesthe peak of the response. The ratio of the two is used to determine theresponse size.

Data Analysis

Once the data were collected on the VIPR, they were archived anduploaded, in reduced form, to Mod3. Once in Mod3, each individual assayplate was QC'ed (looking for acceptable window and dynamic range).

Herg Assay

hERG-inhibition was assayed in a Chinese Hamster Lung cell line (CHL)stably transduced with the structural gene for hERG. Cells express highnumbers of hERG channels resulting in 500 pA to 1.5nA of hERG outward K⁺currents. The method used a planar patch instrument (IonWorks HT,Molecular Devices) that allowed medium-throughput electrophysiologymeasurements in 384-well format. The potency of hERG inhibition wasmeasured at 1.1 μM, 3.3 μM, 10 μM, and 30 μM of the compound studied.The compound was added from a 3× aqueous addition buffer.

The compounds of the present invention exhibit a desirably low activityagainst hERG.

CYP-450 Isozyme Assay

Compound Preparation:

-   1. The desired compound was plated (2 mM in 75% DMSO/25% H₂O) with a    Pieso Sample Distribution Robot (PSDR™) at 8mL per well.-   2. The compound was centrifuged briefly at approximately 1000 rpm to    shift the compound drop to the bottom of the well.-   3. PVP 10K (excipient, 0.2% in 75% DMSO/25% H₂O) was plated with a    PSDR™ at 100 nL per well.-   4. The compound and PVP 10K were centrifuged briefly at    approximately 1000 rpm to ensure an adequate mix of compound and    excipient.-   5. The dry-down of the plates was initiated using house vacuum for    at least 3 hours.-   6. The plates were transferred to a high vacuum (50 millitorr)    apparatus and the dry-down process was continued for at least 15    hours.

The following assay protocol was employed for a desired CYP-450 isozyme(CYP3A4, CYP2C9, CYP1A2, CYP2C19, or CYP2D6).

Assay Protocol

All reagents below were added using a Flying Reagent Dispenser (FRD™).

-   1. 800 nL of dH₂O was added to the 100% activity control, compound,    and background control wells.-   2. 800 nL of the appropriate control drug (3A4:clotrimazole,    2C9:miconazole, 1A2:ticlopidine, 2C19:lansoprazole, or    2D6:propanolol; 10 uM final dissolved in dH₂O) was added to the drug    control wells.-   3. 200 nL of 500 mM K⁺ Phosphate buffer (pH 8.4) was added to the    100% activity control, drug control, and compound wells.-   4. 600 nL of Control Insect Baculosomes (PanVera P2315) in 500 mM K⁺    Phosphate Buffer (pH 8.4) was added to the background control wells.    The calculation for this reagent was based on the protein    concentration of the 100% activity control wells.-   5. The plate was scanned for compound fluorescence using a    NanoPlate™ Fluorescence Plate Reader (NPR™).-   6. 200 mL of NADP⁺ (Sigma, 100 μM final) and substrate in 100 mM K⁺    Phosphate buffer (50 mM K⁺ Phosphate buffer for 2C9 and 2C19) was    added to all wells. Fluorogenic substrate (3A4:5 μM Vivid™ 3A4 Red,    2C9:1 μM Vivid™ 2C9 Green, 1A2:2 μM Vivid™ 1A2 Blue, 2C19:10 μM    Vivid™ 2C19 Blue, and 2D6: 10 μM Vivid™ 2D6 Blue) was added at a    final concentration corresponding to the K_(m) of the substrate for    its pertinent CYP450 isozyme.-   7. 400 nL of the desired CYP450 isozyme and recycling buffer (3.3 mM    glucose-6-phosphate, 0.4 units/ml glucose-6-phosphate dehydrogenase,    100 mM MgCl₂, and 0.00025% Antifoam 289; reagents obtained from    Sigma) in 100 mM K⁺ Phosphate Buffer (50 mM K⁺ Phosphate buffer for    2C9 and 2C19) were added to the 100% activity control, drug control,    and compound wells. The desired isozyme was added to obtain the    following final concentrations of the desired isozyme: 5 nM CYP3A4,    10 nM CYP2C9, 5 nM CYP1A2, 5 nM CYP2C19, or 20 nM CYP2D6.-   8. The plate was incubated for 60 minutes at room temperature.-   9. The plate was scanned for solution fluorescence using a    NanoPlate™ Fluorescence Plate Reader (NPR™).-   10. The NPR™ data was converted into a format compatible with    importation into a data visualizer and complete the analysis of data    acquired.

The compounds of the present invention exhibit a desirably low activityagainst one or more of the CYP450 isozymes.

The activity of selected compounds of the present invention against NaV1.8 channel is shown below in Table 4. In Table 4, the symbols have thefollowing meaning:

“+++” means <2 μM; “++” means between 2 μM and 10 μM; and “+” means >10μM.

TABLE 4 Cmpd # IC50 101 +++ 102 ++ 103 + 104 + 105 ++ 106 + 107 ++ 108++ 109 ++ 110 + 111 + 112 + 113 ++ 114 ++ 115 + 116 ++ 117 ++ 118 ++119 + 120 ++ 121 ++ 122 ++ 123 + 124 + 125 + 126 + 127 +++ 128 ++ 129 +130 + 131 + 132 ++ 133 ++ 134 ++ 135 +++ 136 + 137 ++ 138 + 139 ++ 140 +141 + 142 ++ 143 ++ 144 ++ 145 + 146 + 147 ++ 148 ++ 149 + 150 + 151 +152 + 153 ++ 154 + 155 + 156 ++ 157 ++ 158 + 159 ++ 160 + 162 ++ 163 ++164 + 165 ++ 166 + 167 + 168 ++ 169 + 170 + 172 + 173 + 174 ++ 175 +176 + 177 ++ 178 + 179 + 180 ++ 181 + 182 ++ 183 ++ 184 ++ 185 ++ 186+++ 187 ++ 188 +++ 189 ++ 190 ++ 191 +++ 192 ++ 193 +++ 194 + 195 +++196 +++ 197 +++ 201 ++ 203 + 204 + 205 + 206 ++ 207 +++ 208 +++ 210 ++211 + 212 + 213 + 214 + 215 + 216 + 217 + 218 ++ 219 +++ 220 + 221 +222 + 223 + 224 + 225 + 226 + 227 + 228 + 229 + 230 ++ 231 ++ 232 ++233 + 234 + 235 ++ 236 + 237 + 238 + 239 + 240 + 241 + 242 ++ 243 +244 + 245 + 246 + 247 + 248 ++ 249 ++ 250 +++ 251 ++ 252 + 253 + 254 ++255 + 256 ++ 257 ++ 258 +++ 259 +++ 260 +++ 261 ++ 262 ++ 264 + 265 +266 ++ 267 + 268 + 269 + 270 ++ 271 + 272 ++ 273 ++ 274 ++ 275 ++ 276 ++277 ++ 278 + 279 ++ 280 ++ 281 ++ 282 +++ 283 +++ 301 ++ 302 + 303 ++304 + 305 ++ 306 + 307 + 308 + 309 +++ 310 ++ 311 +++ 312 ++ 314 ++315 + 316 + 317 ++ 318 + 319 ++ 320 ++ 321 + 322 + 323 + 324 + 325 +326 + 327 + 328 + 329 ++ 335 ++ 337 ++ 338 + 339 ++ 340 +++ 342 + 345 ++346 ++ 347 + 348 + 349 + 350 + 351 ++ 352 + 353 + 354 ++ 355 + 356 +357 + 358 + 359 + 360 + 361 ++ 362 + 363 ++ 364 +++ 365 +++ 366 ++ 367+++ 368 ++ 369 +++ 370 +++ 371 +++ 372 +++ 373 ++ 374 + 375 + 376 + 377++ 401 + 402 + 403 + 404 + 405 + 406 + 407 + 408 + 409 + 410 + 411 ++412 + 413 ++ 414 ++ 415 ++ 416 + 417 + 418 ++ 419 ++ 420 +++

1. A compound selected from the group consisting of:


2. A pharmaceutical composition comprising a compound according to claim1, and a pharmaceutically acceptable carrier.
 3. A method for treatingor lessening the severity of a disorder or condition selected fromacute, chronic, neuropathic, or inflammatory pain, or severe pain saidmethod comprising the step of administering to said patient an effectiveamount of a composition according to claim
 2. 4. The method according toclaim 3, wherein the condition or disorder is back pain, head pain, orneck pain.
 5. The method according to claim 3, wherein the condition ordisorder is severe pain, acute pain, postsurgical pain, back pain, orcancer pain.